JP5704788B2 - Combined immunogene therapy and chemotherapy for the treatment of cancer and hyperproliferative diseases - Google Patents
Combined immunogene therapy and chemotherapy for the treatment of cancer and hyperproliferative diseases Download PDFInfo
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- JP5704788B2 JP5704788B2 JP2007545497A JP2007545497A JP5704788B2 JP 5704788 B2 JP5704788 B2 JP 5704788B2 JP 2007545497 A JP2007545497 A JP 2007545497A JP 2007545497 A JP2007545497 A JP 2007545497A JP 5704788 B2 JP5704788 B2 JP 5704788B2
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Abstract
Description
発明の属する分野
本発明は、核酸、遺伝子送達ポリマー、および少なくとも一つの補助的な化学療法薬を含む、哺乳動物の癌または過剰増殖性疾患を治療するための医薬組成物に関する。本発明は、哺乳動物の癌または過剰増殖性疾患を治療する方法にも関し、この方法は、癌細胞またはいずれかその他の過剰増殖性細胞を、腫瘍内注射、腹腔内注射または全身性注射により前記組成物と接触させることを含む。
The present invention relates to a pharmaceutical composition for treating a cancer or hyperproliferative disease in a mammal comprising a nucleic acid, a gene delivery polymer, and at least one adjuvant chemotherapeutic agent. The present invention also relates to a method of treating a cancer or hyperproliferative disease in a mammal, wherein the method comprises cancer cells or any other hyperproliferative cells by intratumoral, intraperitoneal or systemic injection. Contacting with the composition.
発明の背景
癌は、世界の多くの場所において死因のもっとも一般的なものであり、そして250万件以上の癌の症例毎年世界中で診断されている。癌の分子生物学の我々の理解における最近の進歩により、癌が病気の細胞の異常増殖を引き起こす遺伝的疾患であることが示された。したがって、癌治療専門家は、現在、治療用タンパク質そのものではなく、遺伝情報を保持する高分子が関与する治療戦略に注目しており、それにより、外来性で送達される遺伝子を腫瘍環境中で発現させることができる。遺伝子治療は、従来のアプローチではできない多数の方法で、治療による利益を癌患者に対してもたらすと考えられる。伝統的な低分子薬は、しばしば、細胞標的と非特異的相互作用することにより機能し、望ましくない副作用を生じ、そして疾患の根元を治療しない。過去数年間にわたって導入されてきたタンパク質薬は、それらが迅速に分解されそして高用量が必要とされ、それによりしばしば望ましくない副作用を引き起こすため、それ自体に限界を有している。遺伝子治療は、生体自体の細胞機構を使用して、単回注射後は、持続的に治療レベルのタンパク質を、特異的な組織および細胞において生成し、それにより、よりよい患者の適応性とともに、安全かつ効果的な治療方法を提供する。
BACKGROUND OF THE INVENTION Cancer is the most common cause of death in many parts of the world and more than 2.5 million cancer cases are diagnosed worldwide each year. Recent advances in our understanding of the molecular biology of cancer have shown that cancer is a genetic disorder that causes abnormal growth of diseased cells. Therefore, cancer treatment specialists are now focusing on therapeutic strategies involving macromolecules that retain genetic information rather than the therapeutic protein itself, thereby allowing exogenously delivered genes to be present in the tumor environment. Can be expressed. Gene therapy is believed to provide therapeutic benefits to cancer patients in a number of ways not possible with conventional approaches. Traditional small molecule drugs often function by non-specific interactions with cellular targets, produce undesirable side effects, and do not treat the root of the disease. Protein drugs that have been introduced over the past few years have their own limitations because they are rapidly degraded and high doses are required, thereby often causing undesirable side effects. Gene therapy uses the body's own cellular mechanisms to produce sustained therapeutic levels of protein in specific tissues and cells after a single injection, thereby improving patient fitness, Provide safe and effective treatment methods.
一般的に適用される癌遺伝子治療戦略には、1)局所注射、2)局所領域の注射、または3)全身性注射により達成される、免疫療法、細胞除去、および抗-血管形成が含まれる。癌免疫療法は、癌細胞に対する免疫系を刺激することにより癌をたたくための強力なアプローチである。免疫性サイトカインは、免疫細胞を活性化し、成熟させ、そして分化させることにより、宿主免疫応答の発生において重要な役割を果たしている。いくつかのサイトカインは、ヒトにおいてそして癌の動物モデルにおいて、様々な癌に対して試験されてきた(Hum Gene Ther., 1998, vol. 9, 2223;Gene Ther. 1999, vol. 6, 833;Cancer Gene Ther. 2000, vol. 7, 1156;J. Control ReI. 2003, vol. 87, 177;そしてCancer Res., 2002, vol. 62, 4023を参照)。インターロイキン-12(IL-12)は、ヒトの癌の治療においてただいた可能性が示される免疫促進性サイトカインである(The Oncologist, 1996, vol. 1, 88を参照)。IL-12は、2本の共有結合した鎖、p35とp40とからなる70-kDのヘテロ二量体である。IL-12の生物学的作用には、CD4+ T細胞、CD8+ T細胞、およびナチュラルキラー(NK)細胞を休止させおよび活性化させることにより、IFN-γ産生を誘導することが含まれる。IL-12はまた、活性化T細胞および活性化NK細胞の増殖を亢進させ、NK/リンホカイン-活性化キラー細胞の溶解活性を増大させ、そして特異的細胞傷害性Tリンパ球(CTL)反応を促進する。 Commonly applied cancer gene therapy strategies include immunotherapy, cell depletion, and anti-angiogenesis achieved by 1) local injection, 2) local area injection, or 3) systemic injection . Cancer immunotherapy is a powerful approach to knock cancer by stimulating the immune system against cancer cells. Immune cytokines play an important role in the development of host immune responses by activating, maturing, and differentiating immune cells. Several cytokines have been tested against various cancers in humans and in animal models of cancer (Hum Gene Ther., 1998, vol. 9, 2223; Gene Ther. 1999, vol. 6, 833; Cancer Gene Ther. 2000, vol. 7, 1156; J. Control ReI. 2003, vol. 87, 177; and Cancer Res., 2002, vol. 62, 4023). Interleukin-12 (IL-12) is an immunostimulatory cytokine that has shown potential in the treatment of human cancer (see The Oncologist, 1996, vol. 1, 88). IL-12 is a 70-kD heterodimer composed of two covalently linked chains, p35 and p40. The biological effects of IL-12 include inducing IFN-γ production by resting and activating CD4 + T cells, CD8 + T cells, and natural killer (NK) cells. IL-12 also enhances the proliferation of activated T cells and activated NK cells, increases the lytic activity of NK / lymphokine-activated killer cells, and induces specific cytotoxic T lymphocyte (CTL) responses Facilitate.
動物モデルにおいて、組換えIL-12は、深在性のT-細胞により媒介される抗腫瘍作用を誘導し、確立された腫瘍の退縮を引き起こし、その後全身性の免疫記憶が生じたことが示された(The Oncologist, 1996, vol. 1, 88を参照)。しかしながら、組換えIL-12の全身性投与は、結果として、いくつかの研究試験においてそして初期ヒト試験において、用量限度の毒性を引き起こした(Lab Invest., 1994, vol. 71, 862;Science, 1995, vol. 270, 908;J. Interferon Cytokine Res., 1995, vol. 14, 335を参照)。用量限度の毒性は、最近のヒトの臨床試験において、組換えIL-12の腹腔内投与により観察された(Clin. Cancer Res., 2002, vol. 8, 3686)。治療レベルのIL-12を腫瘍部位に局所的に提供することができる遺伝子送達アプローチは、全身性毒性を引き起こすことなく、抗癌反応を生成するという利点を有する。 In animal models, recombinant IL-12 induces anti-tumor effects mediated by deep T-cells, leading to established tumor regression, followed by systemic immune memory (See The Oncologist, 1996, vol. 1, 88). However, systemic administration of recombinant IL-12 resulted in dose-limiting toxicity in some research studies and in early human studies (Lab Invest., 1994, vol. 71, 862; Science, 1995, vol. 270, 908; see J. Interferon Cytokine Res., 1995, vol. 14, 335). Dose limit toxicity has been observed in recent human clinical trials by intraperitoneal administration of recombinant IL-12 (Clin. Cancer Res., 2002, vol. 8, 3686). A gene delivery approach that can provide therapeutic levels of IL-12 locally to the tumor site has the advantage of generating an anti-cancer response without causing systemic toxicity.
ウィルス遺伝子送達システムおよび非ウィルス性遺伝子送達システムの両方とも、癌の動物モデルにおけるIL-12遺伝子送達のために使用された。ウィルス性のアプローチは、主として、癌の発生が高まり、そして宿主免疫によりウィルス性抗原に対する強力な免疫応答が生じるための、毒性の懸念のため、重大な実務上の制限がある。非ウィルス性遺伝子送達システムの開発には、それらの毒性がより少ないことから、かなりな注目が寄せられている。ポリビニルピロリドン(PVP)を使用して、腎臓癌(Renca)および結腸細胞癌(CT26)を治療するためのIL-12の送達用の非ウィルス性遺伝子送達システムが、示された(Gene Ther., 1999, vol. 6, 833を参照)。腫瘍をこの遺伝子治療に供した場合、それらは、たとえば、主要組織適合複合体(MHC)クラスI分子の発現の増加を伴う、NK細胞、CD4およびCD8 T細胞の浸潤の増加など、IL-12タンパク質療法の特徴すべてを示した。IL-12遺伝子送達は、十分に耐用性のものであり、そしてRenca腫瘍を有する動物およびCT26腫瘍を有する動物の両方ともに対して非常に有効であった。腫瘍を拒絶するマウスは、それに引き続く免疫化からも保護されたことから、持続的な全身性免疫の存在が示唆される。官能化されそして低毒性の水溶性リポポリマー(WSLP)を、IL-12遺伝子をCT26結腸癌腫腫瘍へと送達することについて試験した(Mahato et al, Mol. Ther., 2001, vol. 4, 130を参照)。IL-12プラスミド(pIL-12)およびWSLP(pIL-12/WSLP)処置により、むき出しのDNAの場合と比較して、より高い腫瘍内遺伝子発現が得られた。 Both viral and non-viral gene delivery systems have been used for IL-12 gene delivery in animal models of cancer. Viral approaches have significant practical limitations due to toxicity concerns, primarily due to increased cancer development and host immunity resulting in a strong immune response to viral antigens. The development of non-viral gene delivery systems has received considerable attention because of their less toxicity. A non-viral gene delivery system for delivery of IL-12 to treat kidney cancer (Renca) and colon cell carcinoma (CT26) using polyvinylpyrrolidone (PVP) has been demonstrated (Gene Ther., 1999, vol. 6, 833). When tumors are subjected to this gene therapy, they may be affected by IL-12, such as increased NK cell, CD4 and CD8 T cell infiltration with increased expression of major histocompatibility complex (MHC) class I molecules. All the features of protein therapy were shown. IL-12 gene delivery was well tolerated and was very effective against both animals with Renca tumors and animals with CT26 tumors. Mice that reject the tumor were also protected from subsequent immunization, suggesting the presence of persistent systemic immunity. Functionalized and less toxic water soluble lipopolymer (WSLP) was tested for delivering the IL-12 gene to CT26 colon carcinoma tumors (Mahato et al, Mol. Ther., 2001, vol. 4, 130). See). IL-12 plasmid (pIL-12) and WSLP (pIL-12 / WSLP) treatment resulted in higher intratumoral gene expression compared to bare DNA.
さらに、サイトカインIL-12生成の二次的効果、すなわちIFN-γレベルおよび一酸化窒素(NO)レベルもまた、むき出しのDNAと比較した場合、WSLP処置腫瘍においてより高かった。pIL-12/WSLP複合体の単回注射により、腫瘍増殖および動物の生存率に対して最高に準ずる効果を生みだしたが、一方、繰り返し送達により、よりよい効率が得られたことから、このシステムによる送達が不十分であることが示される(J. Control Release 2003, vol. 87, 177)。同様に、別のポリマー性キャリアPAGA中でのIL-12プラスミドの腫瘍内注射により、CT26腫瘍の部分的な阻害しか得られなかった(Gene Ther., 2002, vol. 9, 1075を参照)。これらの結果から、より効率的な送達システムの要求が保障される。初期の前臨床試験においてそれらが不十分であるにもかかわらず、ポリマー性遺伝子キャリアの優れた分子柔軟性により、より効率的な遺伝子送達システムの開発のために不可避である、複合体の修飾および新規の官能化が可能になる。 Furthermore, the secondary effects of cytokine IL-12 production, ie IFN-γ levels and nitric oxide (NO) levels, were also higher in WSLP treated tumors when compared to bare DNA. A single injection of the pIL-12 / WSLP complex produced the most similar effect on tumor growth and animal survival, whereas the repeated delivery resulted in better efficiency, so this system Is shown to be inadequate (J. Control Release 2003, vol. 87, 177). Similarly, intratumoral injection of IL-12 plasmid in another polymeric carrier PAGA provided only partial inhibition of CT26 tumors (see Gene Ther., 2002, vol. 9, 1075). These results ensure a demand for a more efficient delivery system. Despite their deficiencies in early preclinical studies, complex modification and inefficiency for the development of more efficient gene delivery systems due to the superior molecular flexibility of polymeric gene carriers New functionalization becomes possible.
癌に対して単回治療ストラテジーを利用することは、この疾患が多因子の性質を有するため、一般的には有効ではないと、幅広く認識されている。1より多い薬物を組み合わせて抗癌反応を最大化することは、ますます利用されている(Gene Ther., 2000, vol. 11, 1852を参照)。IL-12遺伝子治療とIFN-α遺伝子治療との間に相乗的関係が存在することが示された。これら2種の遺伝子によりRenca腫瘍を同時治療すると、100%の腫瘍拒絶が生じ、それはIL-12(58%)単独またはIFN-α(25%)単独のいずれかの治療により得られたものよりも高かった。同様に、CT26腫瘍は、組み合わせ遺伝子治療により50%の拒絶率を示し、これはIL-12の単回治療およびIFN-αの単回治療から得られる、それぞれ17%の拒絶率および0%の拒絶率よりも高かった。組み合わせ療法により処置された腫瘍は、単回遺伝子治療により処置された腫瘍と比較した場合、NK細胞およびCD8 T細胞の腫瘍浸潤の増加を示した。化学療法とともに幹細胞中にメチルグアニン-DNA-メチルトランスフェラーゼ(MGMT)を遺伝子輸送することにより、正常な細胞を化学療法から保護し、そして化学療法の全身性毒性を減じた(Nature Reviews Cancer 2004, vol. 4, 296)。 The use of a single treatment strategy for cancer is widely recognized as generally ineffective due to the multifactorial nature of the disease. Increasing use of more than one drug to maximize the anticancer response is increasingly being used (see Gene Ther., 2000, vol. 11, 1852). It has been shown that a synergistic relationship exists between IL-12 gene therapy and IFN-α gene therapy. Simultaneous treatment of Renca tumors with these two genes resulted in 100% tumor rejection, compared to that obtained with either IL-12 (58%) alone or IFN-α (25%) alone It was also expensive. Similarly, CT26 tumors showed a 50% rejection rate with combined gene therapy, which was obtained from a single treatment with IL-12 and a single treatment with IFN-α of 17% and 0%, respectively. It was higher than the rejection rate. Tumors treated with combination therapy showed increased tumor invasion of NK cells and CD8 T cells when compared to tumors treated with single gene therapy. Gene transfer of methylguanine-DNA-methyltransferase (MGMT) into stem cells along with chemotherapy protected normal cells from chemotherapy and reduced systemic toxicity of chemotherapy (Nature Reviews Cancer 2004, vol. 4, 296).
さらに、組み合わせ遺伝子治療は、腫瘍中の抗原提示細胞(APC)上のCD40分子数を、単回治療で達成された数よりも高いレベルに上昇させた。APC上でのCD40の亢進制御の上昇は、抗原提示のためのより高い活性化状態と関連している(Nature, 1998, vol. 393, 480;Nature, 1998, vol. 393, 474;およびNature, 1998, vol. 393, 478を参照)。同様の増加は、ケモカインIP-10およびTCA-3についてのmRNAレベルでみられた。したがって、組み合わせ遺伝子治療は、抗-腫瘍免疫を相乗的に亢進し、そしてこの作用は、腫瘍再感作の研究において持続的であることが見いだされた。同様の組み合わせ遺伝子治療研究は、その他の研究グループによって報告された(Laryngoscope 2001, vol. 111, 815を参照)。株化腫瘍を、pIFN-α/PVP、pEL-2/脂質、またはpIL-12/PVP単独、またはそれらの組み合わせにより処置した。その他の2種類の療法と比較した場合のpIFN-α/PVP組み合わせは、単回処置の場合と比較して、抗腫瘍作用を顕著に増大させた。同一の腫瘍モデルを利用する別の研究において、pIL-12/PVPおよびpIL-2/脂質遺伝子を用いた組み合わせ治療は、単回処置の場合と比較して、顕著に高い抗-腫瘍効果を有することが示された(Arch. Otolaryngol Head Neck Surg, 2001, vol. 127, 1319を参照)。 In addition, combination gene therapy increased the number of CD40 molecules on antigen presenting cells (APCs) in the tumor to a level higher than that achieved with a single treatment. Increased upregulation of CD40 on APC is associated with a higher activation state for antigen presentation (Nature, 1998, vol. 393, 480; Nature, 1998, vol. 393, 474; and Nature , 1998, vol. 393, 478). Similar increases were seen at the mRNA levels for chemokines IP-10 and TCA-3. Thus, combination gene therapy synergistically enhanced anti-tumor immunity and this effect was found to be sustained in tumor resensitization studies. Similar combinatorial gene therapy studies have been reported by other research groups (see Laryngoscope 2001, vol. 111, 815). The established tumors were treated with pIFN-α / PVP, pEL-2 / lipid, or pIL-12 / PVP alone, or combinations thereof. The pIFN-α / PVP combination when compared to the other two therapies significantly increased the anti-tumor effect compared to the single treatment. In another study utilizing the same tumor model, combination therapy with pIL-12 / PVP and pIL-2 / lipid genes has a significantly higher anti-tumor effect compared to single treatment (See Arch. Otolaryngol Head Neck Surg, 2001, vol. 127, 1319).
別の研究において、抗-オンコジーンおよび2型ソマトスタチン受容体(sst2)との直鎖ポリエチレンイミン(PEI)のポリプレックスの腫瘍内注射により、膵臓腫瘍および肝臓への転移の増殖の顕著な阻害をもたらした(Curr Opin Biotechnol, 2002, vol.13, 128)。腫瘍中のsst2のPEI-媒介性送達は、アポトーシスの増加およびcaspase-3の活性化およびポリ(ADP-リボース)経路の活性化を引き起こした。固型腫瘍中へのDNA/PEIポリプレックスの持続的な送達は、ボーラス送達により得られた送達と比較して、より高い発現をもたらした(Gene Ther., 1999, vol. 10, 1659)。デンドリマーを、それぞれFas-LおよびHSV-Iチミジンキナーゼの腫瘍内遺伝子輸送による膵臓癌および肝細胞癌の阻害のために使用した(Gene Ther., 2003, vol. 10, 434;およびGene Ther., 2000, vol. 7, 53を参照)。細胞傷害性薬剤およびサイトカインを使用する化学-免疫療法は、新生物性疾患の処置を改善するための新たなアプローチを提供する。IL-12タンパク質とシクロホスファミド、パクリタキセル、シスプラチン、またはドキソルビシンとの組み合わせの治療的効率は、マウスL1210白血病モデルにおいて研究された(Int. J. Cancer, 1998, vol. 77, 720を参照)。L1210白血病を、IL-12または上述した化学療法剤のいずれか1つを単独で与えることにより処置すると、結果として中程度の抗白血病性効果が得られた。IL-12とシクロホスファミドまたはパクリタキセルとの組み合わせは、これらの薬剤を単独で与えた場合と比較して、抗白血病性効果の増強を何ももたらさなかった。しかしながら、IL-12とドキソルビシンとの組み合わせは、抗白血病性効果を増強したが、一方シスプラチンとの組み合わせは、中程度の亢進効果を有した。
In another study, intratumoral injection of polyplexes of linear polyethylenimine (PEI) with anti-oncogene and
しかしながら、マウスメラノーマMmB 16モデルにおいて、IL-12 + パクリタキセルの組み合わせは、個々の治療よりもより効果的であった(Cancer Lett, 1999, vol. 147, 67)。MB-49膀胱癌およびB16メラノーマにおけるアドリアマイシン、シクロホスファミド、または5-FUと組み合わせたIL-12タンパク質の抗腫瘍性効果が調べられた(Clin. Cancer Res., 1997, vol. 3, 1661を参照)。化学療法と組み合わせる際、IL-12投与により、追加的な毒性を引き起こすことなく、抗腫瘍活性が増大した。IL-12またはシクロホスファミドのいずれかによる処置に対して難治性であるマウスサルコーマMCA207において、組換えIL-12とシクロホスファミドとの組み合わせは、個別の処置と比較して、よりよい抗腫瘍反応をもたらした(J. Immunol, 1998, vol. 160, 1369)。マウス乳腺腫瘍において、静脈内パクリタキセル化学療法と腫瘍内IL-12遺伝子治療(IL-12/WSLP)とを含む組み合わせ治療は、個々の処置と比較して、より効率的であった(Molecular Therapy, 2004, vol. 9, 829を参照)。この組み合わせ治療の利点は、パクリタキセルについて使用される送達ビヒクルに依存した。パクリタキセルとIL-12遺伝子治療との相乗的相互作用は、パクリタキセルがポリマー性製剤中に製剤化された場合に観察された。対照的に、癌治療用のパクリタキセル製剤に幅広く使用されるCremophor EL(Taxol(登録商標))との組み合わせは、相乗的ではなかったことから、観察された利点は、製剤特異的なものであったことが示唆される。 However, in the mouse melanoma MmB 16 model, the combination of IL-12 + paclitaxel was more effective than individual treatment (Cancer Lett, 1999, vol. 147, 67). The antitumor effect of IL-12 protein in combination with adriamycin, cyclophosphamide, or 5-FU in MB-49 bladder cancer and B16 melanoma was investigated (Clin. Cancer Res., 1997, vol. 3, 1661 See). When combined with chemotherapy, IL-12 administration increased antitumor activity without causing additional toxicity. In mouse sarcoma MCA207, which is refractory to treatment with either IL-12 or cyclophosphamide, the combination of recombinant IL-12 and cyclophosphamide is more effective compared to individual treatment. It produced a good anti-tumor response (J. Immunol, 1998, vol. 160, 1369). In mouse mammary tumors, combination therapy including intravenous paclitaxel chemotherapy and intratumoral IL-12 gene therapy (IL-12 / WSLP) was more efficient compared to individual treatments (Molecular Therapy, 2004, vol. 9, 829). The benefits of this combination therapy depended on the delivery vehicle used for paclitaxel. A synergistic interaction between paclitaxel and IL-12 gene therapy was observed when paclitaxel was formulated in a polymeric formulation. In contrast, the observed benefits were formulation specific, as the combination with Cremophor EL (Taxol®), widely used in paclitaxel formulations for cancer treatment, was not synergistic. It is suggested that
遺伝子治療が関与する組み合わせアプローチからの所望の結果を達成するため、適切な遺伝子送達システムの選択が重要である。上述した組み合わせ実験において使用される遺伝子送達システム(Molecular Therapy, 2004, vol. 9, 829)は、水溶性リポポリマー、PEI-コレステロール(WSLP)である。本発明においては、我々は、遺伝子送達システムおよび膜相互作用性リガンド(たとえば、コレステロール)の薬物導体、安全性、および強力性を向上させる用に設計された親水性のポリマーを含有し、それが単独の場合または化学療法剤と組み合わせた場合に、抗癌遺伝子のトランスフェクション活性を促進するように多数の幾何学的構造で配向される、という点において、WSLPとは構造的に別個な、新規クラスのポリマーキャリア(PEG-PEI-コレステロール)を記述する。腫瘍組織中でWSLPと比較した場合のPPCのトランスフェクション活性の有利点は、図1および図2に示す。 The selection of an appropriate gene delivery system is important in order to achieve the desired results from a combinatorial approach involving gene therapy. The gene delivery system (Molecular Therapy, 2004, vol. 9, 829) used in the combination experiments described above is a water soluble lipopolymer, PEI-cholesterol (WSLP). In the present invention, we contain a hydrophilic polymer designed to improve the drug delivery, safety, and strength of gene delivery systems and membrane-interacting ligands (eg, cholesterol), A novel, structurally distinct from WSLP in that it is oriented in multiple geometrical structures to enhance the transfection activity of anti-oncogenes, either alone or in combination with chemotherapeutic agents Describes a class of polymer carriers (PEG-PEI-cholesterol). The advantages of the transfection activity of PPC compared to WSLP in tumor tissue are shown in FIGS.
2種類の化学療法剤または化学療法薬のいずれかおよびサイトカインの組み合わせは、臨床的に調べられた。これらの組み合わせは、より幅広い腫瘍の退縮をもたらしたが、長期間の生存の利点は十分なものとはいえず、そして細胞傷害性が問題となった。このことは、化学療法および組換えタンパク質治療と関連してもともとある全身性毒性のためである。新規のそしてより効果的な組み合わせアプローチを設計して、将来の癌治療を改良しなければならない。本発明において、我々は、ポリマー性キャリアにより送達される核酸ベースの治療剤と少なくとも一つの化学療法剤とを含む癌の治療のための新規の組み合わせアプローチを記述する。 The combination of either two chemotherapeutic agents or chemotherapeutic agents and cytokines has been clinically investigated. These combinations resulted in a broader tumor regression, but the benefits of long-term survival were not sufficient and cytotoxicity became a problem. This is due to the systemic toxicity inherent in chemotherapy and recombinant protein therapy. New and more effective combinatorial approaches must be designed to improve future cancer treatments. In the present invention we describe a novel combinatorial approach for the treatment of cancer comprising a nucleic acid based therapeutic agent delivered by a polymeric carrier and at least one chemotherapeutic agent.
発明の概要
本発明は、癌を治療するための、核酸、遺伝子送達ポリマー、および少なくとも一つの医薬用物質を含む医薬組成物を提供する。さらに、本発明はまた、腫瘍細胞の増殖および転移を阻害するための方法、および核酸、遺伝子送達ポリマー、および少なくとも一つの医薬品を含む医薬組成物のin vivo投与により哺乳動物の生存を改善するための方法を提供する。核酸は、プラスミドDNA、siRNA、センスRNA、アンチセンスRNA、およびリボザイムからなる群から選択される構成成分である。プラスミドDNAは、インターロイキン-2、インターロイキン-4、インターロイキン-7、インターロイキン-12、インターロイキン-15、インターフェロン-α、インターフェロン-β、インターフェロン-γ、コロニー刺激因子、顆粒球-マクロファージ刺激因子、血管新生阻害剤、腫瘍抑制遺伝子、チミジンキナーゼ、eNOS、iNOS、p53、p16、TNF-α、Fas-リガンド、変異オンコジーン、腫瘍抗原、ウィルス性抗原または細菌性抗原からなる群から選択される抗癌または抗-増殖性タンパク質をコードするDNA配列を含有する遺伝子発現システムである。プラスミドDNAは、腫瘍細胞またはその他の過剰増殖性細胞の増殖または維持に関与する(1または複数の)タンパク質を阻害するように設計されたshRNA分子をコードしてもよい。プラスミドDNAは、治療用タンパク質と1または複数のshRNAとを同時にコードしてもよい。さらに、前記組成物の核酸は、プラスミドDNAとセンスRNA、アンチセンスRNAまたはリボザイムを含む合成RNAとの混合物であってもよい。
SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition comprising a nucleic acid, a gene delivery polymer, and at least one medicinal substance for treating cancer. Furthermore, the present invention also provides a method for inhibiting tumor cell growth and metastasis, and to improve mammalian survival by in vivo administration of a pharmaceutical composition comprising a nucleic acid, a gene delivery polymer, and at least one pharmaceutical agent. Provide a way. The nucleic acid is a component selected from the group consisting of plasmid DNA, siRNA, sense RNA, antisense RNA, and ribozyme. Plasmid DNA is interleukin-2, interleukin-4, interleukin-7, interleukin-12, interleukin-15, interferon-α, interferon-β, interferon-γ, colony stimulating factor, granulocyte-macrophage stimulation Selected from the group consisting of factors, angiogenesis inhibitors, tumor suppressor genes, thymidine kinase, eNOS, iNOS, p53, p16, TNF-α, Fas-ligand, mutant oncogenes, tumor antigens, viral antigens or bacterial antigens A gene expression system containing a DNA sequence encoding an anti-cancer or anti-proliferative protein. The plasmid DNA may encode an shRNA molecule designed to inhibit the protein (s) involved in the growth or maintenance of tumor cells or other hyperproliferative cells. The plasmid DNA may simultaneously encode the therapeutic protein and one or more shRNAs. Further, the nucleic acid of the composition may be a mixture of plasmid DNA and sense RNA, antisense RNA or synthetic RNA containing ribozyme.
遺伝子送達ポリマーは、カチオン性ポリマーまたは非-縮合性ポリマーである。カチオン性ポリマーは、ポリリジン、ポリエチレンイミン、ポリエチレンイミン(PEI)の官能化誘導体、ポリプロピレンイミン、アミノグリコシド-ポリアミン、ジデオキシ-ジアミノ-b-シクロデキストリン、スペルミンおよびスペルミジンからなる群から選択される。本発明のために適したカチオン性遺伝子送達ポリマーの一例は、PEIバックボーン、脂質、および親水性のポリマースペーサーを含むPEI誘導体である。ここで、脂質は、ポリエチレンイミンバックボーンに対して直接結合するか、またはポリエチレングリコールスペーサーに共有結合し、これが次に、生体適合性結合を介してPEIに対して結合する。本発明のカチオン性遺伝子送達ポリマーは、抗体または抗体フラグメント、細胞受容体、増殖因子受容体、サイトカイン受容体、葉酸、トランスフェリン、上皮増殖因子(EGF)、インスリン、アシアロオロソムコイド、マンノース-6-ホスフェート(単球)、マンノース(マクロファージ、いくつかのB細胞)、ルイスxおよびシアリルルイスx(内皮細胞)、N-アセチルラクトサミン(T細胞)、ガラクトース(結腸癌細胞)、そしてトロンボモジュリン(マウス肺内皮細胞)、ポリミキシンBおよびヘマグルチニンHA2などの融合誘導因子(fusogenic agents)、lysosomotropic agents、T-抗原などの核局在シグナル(NLS)などを含む標的化成分をさらに含んでもよい。別の遺伝子送達ポリマーは、ポリビニルピロリドン、ポリビニルアルコール、ポリ(ラクチド-co-グリコリド)(PLGA)およびPLGAとPEGとのトリブロックコポリマーを含む群から選択される非-縮合性ポリマーである。遺伝子送達ポリマーは、非-縮合性ポリマーであってもよい。そのような非-縮合性ポリマーの例には、ポリビニルピロリドン、ポリビニルアルコール、ポロキサマー、ポリグルタメート、ゼラチン、ポリホスホエステル、シルク-エラスチン-様ハイドロ、アガロースハイドロゲル、脂質微少管、ポリ(ラクチド-co-グリコリド)およびポリエチレングリコール-結合ポリ(ラクチド-co-グリコリド)が含まれる。 The gene delivery polymer is a cationic polymer or a non-condensable polymer. The cationic polymer is selected from the group consisting of polylysine, polyethyleneimine, functionalized derivatives of polyethyleneimine (PEI), polypropyleneimine, aminoglycoside-polyamine, dideoxy-diamino-b-cyclodextrin, spermine and spermidine. One example of a cationic gene delivery polymer suitable for the present invention is a PEI derivative comprising a PEI backbone, a lipid, and a hydrophilic polymer spacer. Here, the lipid binds directly to the polyethyleneimine backbone or covalently binds to a polyethylene glycol spacer, which in turn binds to PEI via a biocompatible bond. The cationic gene delivery polymer of the present invention is an antibody or antibody fragment, a cell receptor, a growth factor receptor, a cytokine receptor, folic acid, transferrin, epidermal growth factor (EGF), insulin, asialo-orosomucoid, mannose-6-phosphate. (Monocytes), mannose (macrophages, some B cells), Lewis x and sialyl Lewis x (endothelial cells), N-acetyllactosamine (T cells), galactose (colon cancer cells), and thrombomodulin (mouse lung endothelial cells) ), Fusion components such as polymyxin B and hemagglutinin HA2, fusogenic agents, lysosomotropic agents, nuclear localization signals (NLS) such as T-antigen and the like may further be included. Another gene delivery polymer is a non-condensable polymer selected from the group comprising polyvinylpyrrolidone, polyvinyl alcohol, poly (lactide-co-glycolide) (PLGA) and a triblock copolymer of PLGA and PEG. The gene delivery polymer may be a non-condensable polymer. Examples of such non-condensable polymers include polyvinylpyrrolidone, polyvinyl alcohol, poloxamer, polyglutamate, gelatin, polyphosphoester, silk-elastin-like hydro, agarose hydrogel, lipid microtubule, poly (lactide-co -Glycolide) and polyethylene glycol-linked poly (lactide-co-glycolide).
上述の組成物の一態様において、医薬用物質は、タキサン類、プラチナ類、アドリアマイシン類、シクロホスファミド、トポテカン、カルムスチン(BCNU)またはそれらの組み合わせからなる群から選択される化学療法薬である。パクリタキセル、カルボプラチン、トポテカン、ゲムシタビンおよびこれらのいずれかの組み合わせが特に好ましい。 In one embodiment of the above composition, the medicinal substance is a chemotherapeutic agent selected from the group consisting of taxanes, platinums, adriamycins, cyclophosphamide, topotecan, carmustine (BCNU) or combinations thereof. . Paclitaxel, carboplatin, topotecan, gemcitabine and any combination thereof are particularly preferred.
上述した組成物の別の態様において、医薬用物質は、CD20抗体、HER2/neu抗体、抗-VEGF抗体、上皮増殖因子受容体抗体、およびそれらの放射性同位体複合体からなる群から選択される抗癌抗体である。 In another embodiment of the above composition, the medicinal substance is selected from the group consisting of CD20 antibody, HER2 / neu antibody, anti-VEGF antibody, epidermal growth factor receptor antibody, and radioisotope complexes thereof. It is an anticancer antibody.
本発明は、核酸、核酸送達ポリマー、および少なくとも一つの補助的な化学療法薬を含む医薬組成物の腫瘍内投与、腹腔内投与、食道内投与、頭蓋内投与、または全身性投与により、哺乳動物の癌を治療する保父応もまた提供する。哺乳動物の癌は、卵巣、乳腺、脳、頭頸部、肝臓、肺、前立腺、腎臓、結腸、膵臓、甲状腺、膀胱、腹腔、胸腔、および皮膚の原発性腫瘍または転移性腫瘍からなる群から選択される。核酸および遺伝子送達ポリマーは、医薬品の投与の前または後に、腫瘍内投与、腹腔内投与、気管内投与または経口投与または全身性投与により投与する。たとえば、いくつかの事例において、医薬用物質(たとえば、化学療法剤)の前に、腫瘍の医薬用物質に対する感受性を潜在的に高め、そして抗-癌反応をブーストするためのものとして、核酸(たとえば、pIL-12 DNA/ポリマー)を投与することが好ましい。別の事例において、遺伝子送達(たとえば、pIL-12/PPC)の前に、医薬用物質(たとえば、化学療法剤)を投与して、医薬用物質が、腫瘍の破壊および後に治療用遺伝子(たとえば、pIL-12/ポリマー)により標的となる癌に対して非常に特異的で頑健な治療反応(たとえば、免疫反応)を誘引するために使用される腫瘍抗原の放出を引き起こすことができることが、好ましい。 The present invention relates to a mammal by intratumoral, intraperitoneal, intraesophageal, intracranial, or systemic administration of a pharmaceutical composition comprising a nucleic acid, a nucleic acid delivery polymer, and at least one adjuvant chemotherapeutic agent. It also provides a paternal treatment to treat other cancers. Mammalian cancer is selected from the group consisting of ovary, breast, brain, head and neck, liver, lung, prostate, kidney, colon, pancreas, thyroid, bladder, abdominal cavity, thoracic cavity, and primary or metastatic tumors of the skin Is done. Nucleic acids and gene delivery polymers are administered by intratumoral, intraperitoneal, intratracheal or oral or systemic administration before or after administration of the pharmaceutical agent. For example, in some cases, prior to a medicinal substance (eg, a chemotherapeutic agent), the nucleic acid (as intended to potentially increase the sensitivity of the tumor to the medicinal substance and boost the anti-cancer response) For example, it is preferred to administer pIL-12 DNA / polymer). In another instance, prior to gene delivery (eg, pIL-12 / PPC), a pharmaceutical substance (eg, a chemotherapeutic agent) is administered so that the pharmaceutical substance is destroyed and subsequently treated with a therapeutic gene (eg, , PIL-12 / polymer) is preferably capable of causing the release of tumor antigens used to elicit very specific and robust therapeutic responses (eg immune responses) against the targeted cancer .
前記医薬組成物(核酸+遺伝子送達ポリマーおよび1またはそれ以上の化学療法剤)による腫瘍の治療により、結果として腫瘍の収縮と寿命の延長が引き起こされる。本発明の方法にしたがった遺伝子治療(核酸と遺伝子送達ポリマー)と化学療法(化学療法剤)との組み合わせにより、付加的効果および/または相乗的効果がもたらされる。本発明の方法の効果は、腫瘍サイズの収縮または腫瘍密度の低下、リンパ球計測数の増加または好中球計測数の増加、または生存の改善、または上記のすべてとして定義されるが、これらには限定されない。さらに、本発明の方法にしたがった遺伝子治療(核酸および遺伝子送達ポリマー)と化学療法(化学療法剤)との組み合わせにより、化学療法剤の毒性が低下し、腫瘍の化学療法に対する耐性が逆転する。本明細書における毒性は、異常な血液学または血清化学または臓器毒性を含む(しかしこれらに限定されない)、臨床的な知見に対する治療に関連する何らかの有害作用として定義される。さらに、本発明にしたがった遺伝子治療(核酸および遺伝子送達ポリマー)と最適以下の用量の化学療法(化学療法剤)との組み合わせにより、最適用量の化学療法剤により達成される抗ガン作用と同等レベルにまでまたはそれよりも高いレベルにまで抗癌作用を亢進するが、毒性は少ない。 Treatment of the tumor with the pharmaceutical composition (nucleic acid + gene delivery polymer and one or more chemotherapeutic agents) results in tumor shrinkage and increased lifespan. The combination of gene therapy (nucleic acid and gene delivery polymer) and chemotherapy (chemotherapeutic agent) according to the method of the present invention provides additional and / or synergistic effects. The effects of the methods of the invention are defined as, but not limited to, shrinking tumor size or decreasing tumor density, increasing lymphocyte count or increasing neutrophil count, or improving survival, or all of the above. Is not limited. Furthermore, the combination of gene therapy (nucleic acid and gene delivery polymer) and chemotherapy (chemotherapeutic agent) according to the method of the invention reduces the toxicity of the chemotherapeutic agent and reverses the resistance of the tumor to chemotherapy. Toxicity herein is defined as any adverse effect associated with treatment for clinical findings, including but not limited to abnormal hematology or serum chemistry or organ toxicity. In addition, the combination of gene therapy (nucleic acid and gene delivery polymer) according to the present invention with a suboptimal dose of chemotherapy (chemotherapeutic agent) provides a level equivalent to the anti-cancer effect achieved by the optimal dose of chemotherapeutic agent. Enhances the anti-cancer effect to a level up to or above, but is less toxic.
組み合わせ治療において、核酸は、プラスミドDNA、siRNA、センスRNA、アンチセンスRNA、およびリボザイムからなる群から選択される構成成分である。核酸は、インターロイキン-2、インターロイキン-4、インターロイキン-7、インターロイキン-12、インターロイキン-15、インターフェロン-α、インターフェロン-β、インターフェロン-γ、コロニー刺激因子、顆粒球-マクロファージ刺激因子、血管新生阻害剤、腫瘍抑制遺伝子、チミジンキナーゼ、eNOS、iNOS、p53、p16、TNF-α、Fas-リガンド、変異オンコジーン、腫瘍抗原、ウィルス性抗原または細菌性抗原からなる群から選択される抗癌または抗-増殖タンパク質をコードするDNA配列を含有する。プラスミドに基づく遺伝子発現システムであってもよい。プラスミドDNAは、腫瘍細胞またはその他の過剰増殖性細胞の増殖または維持に関与する(1または複数の)タンパク質を阻害するように設計されたshRNA分子をコードしてもよい。プラスミドDNAは、治療用タンパク質と1またはそれ以上のshRNA分子とを同時にコードしてもよい。さらに、前記組成物の核酸は、プラスミドDNAと合成RNAとの混合物であってもよい。遺伝子送達ポリマーは、カチオン性ポリマーまたは非-縮合性ポリマーである。カチオン性ポリマーは、ポリリジン、ポリエチレンイミン、ポリエチレンイミンの官能化誘導体、ポリプロピレンイミン、アミノグリコシド-ポリアミン、ジデオキシ-ジアミノ-b-シクロデキストリン、スペルミンおよびスペルミジンを含む群から選択される。本発明のために適したカチオン性遺伝子送達ポリマーの一例は、ポリエチレンイミン(PEI)バックボーン、脂質、およびポリエチレングリコールスペーサーを含むポリエチレンイミン誘導体である。ここで、脂質は、ポリエチレンイミンバックボーンに直接結合するか、またはポリエチレングリコールスペーサーに対して共有結合し、それが次に、生体適合性結合を介して、PEIに対して結合する。本発明のカチオン性遺伝子送達ポリマーは、抗体または抗体フラグメント、細胞受容体、増殖因子受容体、サイトカイン受容体、葉酸、トランスフェリン、上皮増殖因子(EGF)、インスリン、アシアロオロソムコイド、マンノース-6-ホスフェート(単球)、マンノース(マクロファージ、いくつかのB細胞)、ルイスxおよびシアリルルイスx(内皮細胞)、N-アセチルラクトサミン(T細胞)、ガラクトース(結腸癌細胞)、およびトロンボモジュリン(マウス肺内皮細胞)、ポリミキシンBおよびヘマグルチニンHA2などの融合誘導因子(fusogenic agents)、lysosomotrophic agents、T-抗原などの核局在シグナル(NLS)を含む標的化成分をさらに含んでもよい。 In combination therapy, the nucleic acid is a component selected from the group consisting of plasmid DNA, siRNA, sense RNA, antisense RNA, and ribozyme. Nucleic acids are interleukin-2, interleukin-4, interleukin-7, interleukin-12, interleukin-15, interferon-α, interferon-β, interferon-γ, colony stimulating factor, granulocyte-macrophage stimulating factor An angiogenesis inhibitor, a tumor suppressor gene, thymidine kinase, eNOS, iNOS, p53, p16, TNF-α, Fas-ligand, mutant oncogene, tumor antigen, viral antigen or bacterial antigen Contains a DNA sequence encoding a cancer or anti-proliferative protein. It may be a plasmid-based gene expression system. The plasmid DNA may encode an shRNA molecule designed to inhibit the protein (s) involved in the growth or maintenance of tumor cells or other hyperproliferative cells. The plasmid DNA may simultaneously encode a therapeutic protein and one or more shRNA molecules. Furthermore, the nucleic acid of the composition may be a mixture of plasmid DNA and synthetic RNA. The gene delivery polymer is a cationic polymer or a non-condensable polymer. The cationic polymer is selected from the group comprising polylysine, polyethyleneimine, functionalized derivatives of polyethyleneimine, polypropyleneimine, aminoglycoside-polyamine, dideoxy-diamino-b-cyclodextrin, spermine and spermidine. One example of a cationic gene delivery polymer suitable for the present invention is a polyethyleneimine derivative comprising a polyethyleneimine (PEI) backbone, a lipid, and a polyethylene glycol spacer. Here, the lipid is bound directly to the polyethyleneimine backbone or covalently bound to a polyethylene glycol spacer, which in turn binds to PEI via a biocompatible bond. The cationic gene delivery polymer of the present invention is an antibody or antibody fragment, a cell receptor, a growth factor receptor, a cytokine receptor, folic acid, transferrin, epidermal growth factor (EGF), insulin, asialo-orosomucoid, mannose-6-phosphate. (Monocytes), mannose (macrophages, some B cells), Lewis x and sialyl Lewis x (endothelial cells), N-acetyllactosamine (T cells), galactose (colon cancer cells), and thrombomodulin (mouse lung endothelial cells) ), Fusion components such as polymyxin B and hemagglutinin HA2, fusogenic agents, lysosomotrophic agents, targeting components including nuclear localization signals (NLS) such as T-antigens.
遺伝子送達ポリマーは、ポリビニルピロリドン、ポリビニルアルコール、ポリ(ラクチド-co-グリコリド)(PLGA)およびPLGAとPEGとのトリブロックコポリマーを含む群から選択される非-縮合性ポリマーである。化学療法薬は、タキサン類、プラチナ類、アドリアマイシン類、シクロホスファミド、トポテカン、カルムスチン(BCNU)またはこれらの組み合わせからなる群から選択される構成成分である。パクリタキセル、カルボプラチン、トポテカン、ゲムシタビンおよびそれらのいずれかの組み合わせが特に好ましい。 The gene delivery polymer is a non-condensable polymer selected from the group comprising polyvinylpyrrolidone, polyvinyl alcohol, poly (lactide-co-glycolide) (PLGA) and a triblock copolymer of PLGA and PEG. The chemotherapeutic agent is a component selected from the group consisting of taxanes, platinums, adriamycins, cyclophosphamide, topotecan, carmustine (BCNU) or combinations thereof. Paclitaxel, carboplatin, topotecan, gemcitabine and any combination thereof are particularly preferred.
上述した方法の別の態様において、医薬用物質は、CD20抗体、HER2/neu抗体、抗-VEGF抗体、上皮増殖因子受容体抗体およびそれらの放射性同位体複合体からなる群から選択される抗癌抗体である。 In another embodiment of the above method, the medicinal substance is an anticancer selected from the group consisting of CD20 antibody, HER2 / neu antibody, anti-VEGF antibody, epidermal growth factor receptor antibody and their radioisotope complexes. It is an antibody.
本発明はまた、化学療法薬を含まず、プラスミドに基づく遺伝子発現システムおよび遺伝子送達ポリマーを含む医薬組成物の腫瘍内投与、腹腔内投与、気管内投与、頭蓋内投与、または全身性投与により、哺乳動物の癌または過剰増殖性疾患を治療する方法を提供する。哺乳動物の癌は、卵巣、乳腺、脳、頭頸部、甲状腺、肝臓、肺、膵臓、小腸、脾臓、前立腺、腎臓、膀胱、結腸、およびメラノーマの原発性腫瘍および転移腫瘍からなる群から選択される。好ましくは、核酸は、インターロイキン-2、インターロイキン-4、インターロイキン-7、インターロイキン-12、インターロイキン-15、インターフェロン-α、インターフェロン-β、インターフェロン-γ、コロニー刺激因子、顆粒球-マクロファージ刺激因子、血管新生阻害剤、腫瘍抑制遺伝子、チミジンキナーゼ、eNOS、iNOS、p53、p16、TNF-α、Fas-リガンド、変異オンコジーン、腫瘍抗原、ウィルス性抗原または細菌性抗原からなる群から選択される抗癌または抗増殖性タンパク質をコードするDNA配列を含有する、プラスミドに基づく遺伝子発現システムである。プラスミドDNAは、腫瘍細胞またはその他の過剰増殖性細胞の増殖または維持に関連する(1または複数の)タンパク質を阻害するように設計されたshRNA分子をコードしてもよい。プラスミドDNAは、治療用タンパク質と1またはそれ以上のshRNA分子とを同時にコードしてもよい。さらに、前記組成物の核酸は、プラスミドDNAと合成RNAとの混合物であってもよい。 The invention also includes intratumoral, intraperitoneal, intratracheal, intracranial, or systemic administration of a pharmaceutical composition that is free of chemotherapeutic agents and includes a plasmid-based gene expression system and a gene delivery polymer, Methods of treating mammalian cancer or hyperproliferative diseases are provided. The mammalian cancer is selected from the group consisting of primary and metastatic tumors of the ovary, breast, brain, head and neck, thyroid, liver, lung, pancreas, small intestine, spleen, prostate, kidney, bladder, colon, and melanoma. The Preferably, the nucleic acid is interleukin-2, interleukin-4, interleukin-7, interleukin-12, interleukin-15, interferon-α, interferon-β, interferon-γ, colony stimulating factor, granulocyte- Selected from the group consisting of macrophage stimulating factor, angiogenesis inhibitor, tumor suppressor gene, thymidine kinase, eNOS, iNOS, p53, p16, TNF-α, Fas-ligand, mutant oncogene, tumor antigen, viral antigen or bacterial antigen A plasmid-based gene expression system containing a DNA sequence encoding an anti-cancer or anti-proliferative protein. The plasmid DNA may encode an shRNA molecule designed to inhibit protein (s) associated with the growth or maintenance of tumor cells or other hyperproliferative cells. The plasmid DNA may simultaneously encode a therapeutic protein and one or more shRNA molecules. Furthermore, the nucleic acid of the composition may be a mixture of plasmid DNA and synthetic RNA.
前記組成物の遺伝子送達ポリマーは、カチオン性ポリマーまたは非-縮合性ポリマーである。カチオン性ポリマーは、ポリエチレンイミン、ポリエチレンイミンの官能化誘導体、ポリプロピレンイミン、アミノグリコシド-ポリアミン、ジデオキシ-ジアミノ-b-シクロデキストリン、スペルミンおよびスペルミジンからなる群から選択される。提示のために適しているカチオン性ポリマーの一例は、ポリエチレンイミン(PEI)、脂質、および親水性のポリマースペーサーを含むポリエチレンイミン誘導体である。ここで、脂質は、ポリエチレンイミンバックボーンに対して直接結合するかまたは親水性のポリマースペーサーに共有結合し、それが次に、生体適合性結合を介して、PEIに対して結合する。本発明のカチオン性ポリマーは、抗体または抗体フラグメント、細胞受容体、増殖因子受容体、サイトカイン受容体、葉酸、トランスフェリン、上皮増殖因子(EGF)、インスリン、アシアロオロソムコイド、マンノース-6-ホスフェート(単球)、マンノース(マクロファージ、いくつかのB細胞)、ルイスxおよびシアリルルイスx(内皮細胞)、N-アセチルラクトサミン(T細胞)、ガラクトース(結腸癌細胞)、およびトロンボモジュリン(マウス肺内皮細胞)、ポリミキシンBおよびヘマグルチニンHA2などの融合誘導因子(fusogenic agents)、lysosomotrophic agents、T-抗原などの核局在シグナル(NLS)などを含む標的化成分をさらに含んでもよい。別の遺伝子送達ポリマーは、ポリビニルピロリドン、ポリビニルアルコール、ポリ(ラクチド-co-グリコリド)(PLGA)およびPLGAとPEGとのトリブロックコポリマーを含む群から選択される非-縮合性ポリマーである。医薬組成物(核酸+遺伝子送達ポリマーおよび1またはそれ以上の化学療法剤)による腫瘍の治療により、結果として腫瘍の収縮と寿命の延長が引き起こされる。 The gene delivery polymer of the composition is a cationic polymer or a non-condensable polymer. The cationic polymer is selected from the group consisting of polyethyleneimine, a functionalized derivative of polyethyleneimine, polypropyleneimine, aminoglycoside-polyamine, dideoxy-diamino-b-cyclodextrin, spermine and spermidine. One example of a cationic polymer that is suitable for presentation is a polyethyleneimine derivative comprising polyethyleneimine (PEI), a lipid, and a hydrophilic polymer spacer. Here, the lipid is either directly attached to the polyethyleneimine backbone or covalently attached to the hydrophilic polymer spacer, which in turn is attached to PEI via a biocompatible bond. The cationic polymer of the present invention comprises an antibody or antibody fragment, a cell receptor, a growth factor receptor, a cytokine receptor, folic acid, transferrin, epidermal growth factor (EGF), insulin, asialoolomucoid, mannose-6-phosphate (mono Spheres), mannose (macrophages, some B cells), Lewis x and sialyl Lewis x (endothelial cells), N-acetyllactosamine (T cells), galactose (colon cancer cells), and thrombomodulin (mouse lung endothelial cells), It may further comprise targeting components including fusogenic agents such as polymyxin B and hemagglutinin HA2, lysosomotrophic agents, nuclear localization signals (NLS) such as T-antigen, and the like. Another gene delivery polymer is a non-condensable polymer selected from the group comprising polyvinylpyrrolidone, polyvinyl alcohol, poly (lactide-co-glycolide) (PLGA) and a triblock copolymer of PLGA and PEG. Treatment of tumors with a pharmaceutical composition (nucleic acid + gene delivery polymer and one or more chemotherapeutic agents) results in tumor shrinkage and increased lifespan.
発明の詳細な説明
生理活性物質を送達するための本発明の組成物および方法を開示しそして記載する前に、特定の構成、プロセス工程、および材料が幾分変化する可能性があることから、本発明が、本明細書中に開示された特定の構成、プロセス工程、そして材料に限定されないことは、理解されるべきである。本発明の範囲は添付の請求の範囲およびその均等範囲によってのみ限定されるものであるため、本明細書中で使用される用語用法は、特定の態様のみを記載する目的で使用されるものであり、そして限定を意図するものではないこともまた、理解されるべきである。
DETAILED DESCRIPTION OF THE INVENTION Before disclosing and describing the compositions and methods of the present invention for delivering bioactive agents, certain configurations, process steps, and materials may vary somewhat, It is to be understood that the invention is not limited to the specific configurations, process steps, and materials disclosed herein. The terminology used herein is for the purpose of describing particular embodiments only, as the scope of the present invention is limited only by the appended claims and equivalents thereof. It should also be understood that it is and is not intended to be limiting.
本明細書および添付の請求の範囲において使用される場合、単数形(“a”“an”および“the”)には、文脈において明確にそうでないと解釈しているのでなければ、複数の言及が含まれることは注意されなければならない。従って、例えば、“ジスルフィド結合”を含有するポリマーの言及には、2またはそれ以上のその様なジスルフィド結合が含まれ、“リガンド”の言及には、1またはそれ以上のその様なリガンドの言及が含まれ、そして“薬物”の言及には、2またはそれ以上のその様な薬物の言及が含まれる。 As used in this specification and the appended claims, the singular forms “a”, “an” and “the”) include plural references unless the context clearly dictates otherwise. It should be noted that is included. Thus, for example, reference to a polymer containing “disulfide bonds” includes two or more such disulfide bonds, and reference to “ligand” includes reference to one or more such ligands. And reference to “drug” includes reference to two or more such drugs.
本発明を記載しそして請求項に記載する際、以下に記載する定義に従って、以下の用語用法を使用する。
“トランスフェクト”または“トランスフェクション”は、細胞の外部環境から細胞内部環境へ、特に細胞質および/または細胞核に関して核酸を輸送することを意味する。何らかの具体的な理論により縛られないが、1またはそれ以上のカチオン性ポリマー/核酸複合体中にカプセル化するかまたはその様な複合体に対して結合させたのち、またはそれと同調させたのち、細胞に対して送達することができる。特定のトランスフェクションの事例は、核酸を細胞核に送達する。核酸には、DNAおよびRNA、ならびに合成の同様のものが含まれる。その様な核酸には、ミスセンス、アンチセンス、ナンセンス、ならびにタンパク質生成性ヌクレオチド、タンパク質やペプチドや核酸の生成を調節するオン・オフや速度制御型のヌクレオチドが含まれる。特に、限定されないが、それらは、ゲノムDNA、cDNA、mRNA、tRNA、rRNA、ハイブリッド配列、または合成または半合成配列、および天然由来のものまたは人工由来のものであってもよい。さらに、核酸は、オリゴヌクレオチドから染色体までの範囲で、サイズが可変であってもよい。これらの核酸は、ヒト由来、動物由来、植物由来、細菌由来、ウィルス由来、または合成由来であってもよい。それらは、当業者に既知のいずれかの技術により得ることができる。
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below.
“Transfection” or “transfection” means the transport of nucleic acids from the cell's external environment to the cell's internal environment, particularly with respect to the cytoplasm and / or cell nucleus. Without being bound by any particular theory, after encapsulating in or binding to or synchronizing with one or more cationic polymer / nucleic acid complexes, Can be delivered to cells. Particular transfection cases deliver nucleic acids to the cell nucleus. Nucleic acids include DNA and RNA, as well as synthetic equivalents. Such nucleic acids include missense, antisense, nonsense, and proteinogenic nucleotides, as well as on / off and rate-controlled nucleotides that regulate the production of proteins, peptides and nucleic acids. In particular, but not limited to, they may be genomic DNA, cDNA, mRNA, tRNA, rRNA, hybrid sequences, or synthetic or semi-synthetic sequences, and naturally or artificially derived. Furthermore, the nucleic acid may vary in size in the range from oligonucleotide to chromosome. These nucleic acids may be human, animal, plant, bacterial, viral, or synthetic. They can be obtained by any technique known to those skilled in the art.
本明細書中で使用する場合、用語“医薬用物質”または“薬物”、あるいは何らか他の類似の用語は、当該技術分野において以前から知られている方法により、および/または本発明中で教示される方法により、投与するために適したいずれかの化学的物質または化合物または生物学的物質または化合物のことを意味し、所望の生物学的作用または医薬的作用を誘導し、そして(1)生物に対する予防的作用を有し、そして望まれない生物学的作用を予防すること、例えば感染を予防すること、(2)疾患により生じる症状を緩和すること、例えば、疾患の結果として生じる疼痛または炎症を緩和すること、および/または(3)生物から疾患を緩和し、低減しまたは完全に除去することのいずれか、を含んでもよいが、これらには限定されない。この作用は局所的な麻酔作用を提供するものなどの局所的なものであってもよく、またはそれは全身性のものであってもよい。 As used herein, the term “pharmaceutical substance” or “drug”, or some other similar term is used according to methods previously known in the art and / or in the present invention. Means any chemical or compound or biological substance or compound suitable for administration by the method taught, induces the desired biological or pharmaceutical effect, and (1 ) Having a preventive action on the organism and preventing unwanted biological effects, eg preventing infection, (2) alleviating symptoms caused by the disease, eg pain resulting from the disease Or may include, but is not limited to, alleviating inflammation and / or (3) alleviating, reducing or completely eliminating a disease from an organism.This effect may be local, such as providing a local anesthetic effect, or it may be systemic.
本発明は、新規な薬物や、生理活性物質それ自体の新規なクラスについてのものではない。むしろ、本発明は、当該分野の技術水準において存在しまたは活性物質としてその後証明され得、そして本発明により送達するために適している、遺伝子またはその他の生理活性物質の送達のための、生体適合性カチオン性コポリマー組成物、およびその様な組成物を使用する方法に関するものである。その様な物質には、通常生体内に送達される幅広いクラスの化合物が含まれる。一般的には、これには:DNA、RNA、およびオリゴヌクレオチド等の核酸、抗生物質および抗ウィルス薬などの抗-感染薬、鎮痛剤および組合せ鎮痛剤;食欲抑制薬;抗寄生虫薬; 抗関節炎薬;抗ぜんそく薬;抗けいれん薬;抗うつ薬;抗糖尿病薬;抗下痢薬;抗ヒスタミン薬;抗炎症薬;抗片頭痛調製物;抗嘔吐薬;抗新生物薬;抗パーキンソン薬;鎮痒薬;抗精神病薬;解熱剤;抗けいれん薬;抗コリン作動薬;交感神経興奮薬;キサンチン誘導体;カリウムチャンネルブロッカー、カルシウムチャンネルブロッカー、β-ブロッカー、α-ブロッカー、および抗不整脈薬を含む心臓血管調製物;抗高血圧薬;利尿薬および抗利尿薬;全身性、冠状血管性、末梢性、および中枢性のものを含む、血管拡張薬;中枢神経系興奮薬;血管収縮薬;充血除去剤を含む感冒薬;エストラジオール、またはコルチコステロイドを含むその他のステロイド等のホルモン;睡眠薬;免疫抑制薬;筋弛緩薬;副交感神経遮断薬;精神刺激薬;鎮静剤;およびトランキライザー;が含まれるが、これらには限定されない。本発明の方法により、例えば、イオン化、非イオン化、遊離塩基、酸付加塩、等のあらゆる形状の薬物を、高分子量の薬物または低分子量の薬物と同様に送達することができる。送達される生理活性物質の上位概念または下位概念についての唯一の限定は、日常的な実験により容易に決定することができる機能性の限定である。 The present invention is not about a novel drug or a novel class of bioactive substances themselves. Rather, the present invention is biocompatible for the delivery of genes or other bioactive substances that exist in the state of the art or can subsequently be proven as active substances and are suitable for delivery according to the present invention. Cationic cationic copolymer compositions and methods of using such compositions. Such materials include a broad class of compounds that are normally delivered in vivo. In general, this includes: nucleic acids such as DNA, RNA, and oligonucleotides, anti-infectives such as antibiotics and antivirals, analgesics and combination analgesics; appetite suppressants; antiparasitics; antiarthritis Anticonvulsants; Antidepressants; Antidiabetics; Antidiarrheal drugs; Antihistamines; Antiinflammatory drugs; Antimigraine preparations; Antiemetics; Antineoplastics; Antiparkinsonian drugs; Drugs; antipsychotics; antipyretics; anticonvulsants; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium channel blockers, calcium channel blockers, β-blockers, α-blockers, and antiarrhythmic agents Antihypertensives; diuretics and antidiuretics; vasodilators, including systemic, coronary, peripheral, and central; central nervous system stimulants; vasoconstrictors; Cold drugs including drugs; hormones such as estradiol or other steroids including corticosteroids; sleeping drugs; immunosuppressants; muscle relaxants; parasympathomimetic drugs; psychostimulants; sedatives; and tranquilizers However, it is not limited to these. By the method of the present invention, for example, any form of drug such as ionized, non-ionized, free base, acid addition salt, etc. can be delivered in the same manner as a high molecular weight drug or a low molecular weight drug. The only limitation on the superconcept or subconcept of the bioactive substance to be delivered is the functionality limitation that can be easily determined by routine experimentation.
本明細書中で使用される場合、用語“生体適合性の”または“生分解”は、可溶化加水分解、により、または酵素および生物のその他の生成物であってもよい生物学的に形成された構成要素の作用により、物質をあまり複雑ではない中間体または最終生成物へと変換することとして定義される。 As used herein, the term “biocompatible” or “biodegradation” refers to biologically formed, which may be by solubilization hydrolysis or other products of enzymes and organisms. Is defined as the transformation of the material into a less complex intermediate or final product by the action of the constituents made.
本明細書中で使用される場合、“有効量”は、所望の局所的または全身性作用ならびになんらかの医療的処置に伴う適度なリスク/便益比の性能を得るために十分な、核酸または生理活性物質の量を意味する。 As used herein, an “effective amount” is a nucleic acid or bioactivity sufficient to obtain the desired local or systemic effect as well as a moderate risk / benefit performance associated with any medical treatment. Means the amount of a substance.
本明細書中で使用される場合、“ペプチド”は、いずれかの長さのペプチドを意味し、そしてタンパク質を含む。用語“ポリペプチド”および“オリゴペプチド”は、特定のサイズが特に指定されていない限り、何らかの具体的な目的とするサイズ制限なしに使用される。使用することができる典型的なペプチドは、オキシトシン、バソプレッシン、副腎皮質刺激ホルモン、上皮細胞増殖因子、プロラクチン、ルリベリン(luliberin)または黄体形成ホルモン放出ホルモン、成長ホルモン、成長ホルモン放出ホルモン、インスリン、ソマトスタチン、グルカゴン、インターフェロン類、ガストリン、テトラガストリン、ペンタガストリン、ウロガストリン、セクレチン、カルシトニン、エンケファリン、エンドルフィン、アンギオテンシン、レニン、ブラジキニン、バシトラシン、ポリミキシン、コリスチン、チロシジン、グラミシジン(gramicidines)、および合成類似体、修飾物質および薬理学的に活性なそのフラグメント、モノクローナル抗体、および可溶性ワクチン、からなる群から選択されるものである。使用することができるペプチドまたはタンパク質薬物についての唯一の限定は、機能性の一つである。 As used herein, “peptide” means a peptide of any length and includes a protein. The terms “polypeptide” and “oligopeptide” are used without any specific size limit, unless a specific size is specifically specified. Typical peptides that can be used are oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, prolactin, luliberin or luteinizing hormone releasing hormone, growth hormone, growth hormone releasing hormone, insulin, somatostatin, Glucagon, interferons, gastrin, tetragastrin, pentagastrin, urogastrin, secretin, calcitonin, enkephalin, endorphins, angiotensin, renin, bradykinin, bacitracin, polymyxin, colistin, tyrosidine, gramicidines, and synthetic analogues, substances And a pharmacologically active fragment thereof, a monoclonal antibody, and a soluble vaccine. The only limitation on peptide or protein drugs that can be used is one of functionality.
本明細書中で使用される場合、炭水化物の“誘導体”には、例えば、糖の酸型、例えば、グルクロン酸;糖のアミン、例えば、ガラクトサミン;糖のホスフェート、例えば、マンノース-6-リン酸;などが含まれる。 As used herein, “derivatives” of carbohydrates include, for example, sugar acid forms, such as glucuronic acid; sugar amines, such as galactosamine; sugar phosphates, such as mannose-6-phosphate. And so on.
本明細書中で使用される場合、“投与”および類似の用語は、組成物が全身を循環することができ、そこで組成物が標的細胞に結合し、そしてエンドサイトーシスにより取り込まれることができるように、組成物を治療される個体に送達することを意味する。このように、組成物を、好ましくは、全身的に、典型的には皮下経路、筋肉内経路、経皮経路、静脈内経路、または腹腔内経路により、個体に対して投与する。そのような用途のための注射は、溶液またはサスペンジョンとしていずれかの従来の形状で、または注射の前に液体中の溶液またはサスペンジョンとしてまたはエマルジョンとして調製するために適している固体形状で、調製することができる。投与用に使用することができる適した賦形剤には、例えば、水、塩類溶液、デキストロース、グリセロール、エタノールなどが含まれ;そして所望の場合、湿潤剤または乳化剤、バッファーなどの少量の補助物質が含まれる。 As used herein, “administration” and similar terms are such that the composition can circulate systemically, where it can bind to target cells and be taken up by endocytosis. As such, it means delivering the composition to the individual being treated. Thus, the composition is preferably administered to an individual systemically, typically by the subcutaneous, intramuscular, transdermal, intravenous, or intraperitoneal route. Injections for such applications are prepared in any conventional form as a solution or suspension, or in a solid form suitable for preparation as a solution or suspension in liquid or as an emulsion prior to injection. be able to. Suitable excipients that can be used for administration include, for example, water, saline, dextrose, glycerol, ethanol, and the like; and, if desired, minor amounts of auxiliary substances such as wetting or emulsifying agents, buffers, and the like. Is included.
本明細書中で使用する場合、“効果”および同様の用語は、腫瘍の消失または腫瘍の、または腫瘍のサイズの収縮、または腫瘍密度の減少、またはリンパ球数の増加、または好中球数の増加、または生存の改善、またはこれらのすべてを意味する。本明細書中で使用する場合、“毒性”は、異常な血液学、または血清化学的結果、または臓器毒性を含む(しかしこれらには限定されない)臨床的知見に対する、いずれかの治療に関連する有害作用として定義される。 As used herein, “effect” and similar terms refer to tumor disappearance or tumor shrinkage, or tumor size shrinkage, or decrease in tumor density, or increase in lymphocyte count, or neutrophil count. Mean an increase in, or improvement in survival, or all of these. As used herein, “toxicity” refers to any treatment for clinical findings including but not limited to abnormal hematology, or serum chemistry results, or organ toxicity. Defined as an adverse effect.
新たな癌治療ストラテジーは、治療用タンパク質それ自体ではなく、外来性に送達された遺伝子を、腫瘍環境中で発現することができる、遺伝情報を保持する高分子を送達することに焦点を当てる。非-ウィルス性遺伝子送達システムを使用する方法は、ウィルス性送達システムと比較してより安全であると考えられるが、現在のポリマーシステムの実務的な応用は、効率が低いため、満足のいくものではない。水溶性リポポリマー(WSLP)を形成するコレステロールの共有結合により、低分子量PEIの遺伝子トランスフェクション効率が亢進されるストラテジーは、最近開示された(Mol. Ther.、2001、4、130を参照)。固形腫瘍へのWSLPを用いたIL-12遺伝子輸送は、非修飾PEIにより行われるIL-12遺伝子輸送よりも顕著に良好であり、そしてより顕著な腫瘍阻害をもたらした。 New cancer treatment strategies focus on delivering macromolecules that retain genetic information that can express exogenously delivered genes in the tumor environment rather than the therapeutic protein itself. Methods using non-viral gene delivery systems are considered safer compared to viral delivery systems, but the practical application of current polymer systems is satisfactory due to their low efficiency is not. A strategy has been recently disclosed (see Mol. Ther., 2001, 4, 130) where the covalent linking of cholesterol to form water soluble lipopolymer (WSLP) enhances the gene transfection efficiency of low molecular weight PEI. IL-12 gene transport using WSLP to solid tumors was significantly better than IL-12 gene transport performed by unmodified PEI and resulted in more significant tumor inhibition.
本発明は、新規なポリマーシステム、PEG-PEI-コレステロール(PPC)、を提供する。これは、PEG部分を含有し、そして腫瘍中への顕著に高いトランスフェクション効率をもたらす点で、WSLP(PEI-コレステロール)とは異なる(図1)。PEGの付加は、生物学環境中での核酸/ポリマー複合体の安定性を亢進させ、先行技術(WSLP)におけるこの欠点を回避するために設計された。さらに、PEG鎖の付加により、PPC鎖上へのリガンドの取り込みが可能になり、送達の組織選択制が向上される。たとえば、先行技術(WSLP)におけるPEIバックボーンに対して直接的に結合されているコレステロール部分は、PEIバックボーンからさらに伸長されて、細胞受容体相互作用のためのより柔軟性の形状を作製することができる。PEIバックボーンのユニットあたりのPEG分子の数を調節することは、トランスフェクション活性の最適な亢進をもたらすために重要である。図2に示されるように、腫瘍遺伝子輸送の程度は、異なるPPC構成成分、PEG、PEI、およびコレステロールの比率に依存する。組成物の好ましい範囲は、固定化コレステロール含量で、PEG:PEIのモル比が2〜4であった。PEIとコレステロールとの間の最適比率は、1:0.5〜1:1であった。PPCが腫瘍中への遺伝子輸送を促進する能力は、治療用遺伝子を用いて調べられた。マウスIL-12遺伝子を含有する発現プラスミド(pmIL-12)を、窒素(N)対ホスフェート(P)比(N:P比)が11:1でPPCと複合化し、そして固形4T1腫瘍を有するマウス中に腫瘍内で、または腹膜散在性卵巣腫瘍を有するマウス中に腹腔内で、投与した。 The present invention provides a novel polymer system, PEG-PEI-cholesterol (PPC). This differs from WSLP (PEI-cholesterol) in that it contains a PEG moiety and results in a significantly higher transfection efficiency into the tumor (Figure 1). The addition of PEG was designed to enhance the stability of the nucleic acid / polymer complex in the biological environment and avoid this drawback in the prior art (WSLP). Furthermore, the addition of a PEG chain allows the incorporation of a ligand onto the PPC chain and improves the tissue selection regime for delivery. For example, the cholesterol moiety directly attached to the PEI backbone in the prior art (WSLP) can be further extended from the PEI backbone to create a more flexible shape for cell receptor interaction. it can. Controlling the number of PEG molecules per unit of the PEI backbone is important to provide optimal enhancement of transfection activity. As shown in FIG. 2, the extent of oncogene transport depends on the ratio of different PPC components, PEG, PEI, and cholesterol. The preferred range of the composition was immobilized cholesterol content and a PEG: PEI molar ratio of 2-4. The optimal ratio between PEI and cholesterol was 1: 0.5 to 1: 1. The ability of PPC to promote gene transport into tumors was investigated using therapeutic genes. Mice with an expression plasmid containing the mouse IL-12 gene (pmIL-12) complexed with PPC at a nitrogen (N) to phosphate (P) ratio (N: P ratio) of 11: 1 and having a solid 4T1 tumor Administered intratumorally or intraperitoneally into mice with peritoneal diffuse ovarian tumors.
両方の腫瘍モデルにおいて、IL-12遺伝子輸送は、IL-12レベルの上昇により明らかにされた(図3)。腹膜腫瘍保持マウスにおいて、治療後IL-12レベルは、24時間以内に上昇し、そして7日目までにベースラインレベルに減少した。IL-12作用の動力学は、IL-12作用の下流メディエータであるIFN-γの増加と緊密に関連していた(図4)。IFN-γレベルの増加は、予想されたよりも若干遅れ、そして7日後にベースラインより上に上昇したままであった。 In both tumor models, IL-12 gene transport was revealed by elevated IL-12 levels (Figure 3). In peritoneal tumor bearing mice, post-treatment IL-12 levels increased within 24 hours and decreased to baseline levels by day 7. The kinetics of IL-12 action was closely associated with an increase in IFN-γ, a downstream mediator of IL-12 action (Figure 4). The increase in IFN-γ levels was slightly later than expected and remained elevated above baseline after 7 days.
これらのデータは、IL-12発現プラスミドおよびPPCを含む組成物が、異なる腫瘍型において、そして異なる投与経路により、IL-12遺伝子輸送を明らかにすることができることを示す。pmIL-12/PPCにより媒介されるIL-12遺伝子輸送は、腫瘍増殖の顕著な阻害を引き起こすため、治療的に顕著である。腹膜散在性卵巣腫瘍を有するマウスにおいて、10〜250μgのDNA用量でpmIL-12/PPC複合体の腹腔内投与(N:P比11:1)により、用量依存的に、腫瘍負荷を顕著に低下させ(図5)そして生存を向上した(図6)。pmIL-12/PPC(N:P比11:1)の治療効果は、結腸直腸癌においても観察された。腹膜散在性結腸直腸癌を有するマウスにおける25μgのpmIL-12/PPC複合体の腹腔内投与は、非処置動物と比較して、その生存が顕著に延長された(図7)。pmIL-12/PPCによるIL-12遺伝子輸送の抗癌効果は、腫瘍内投与後、固形腫瘍中でも観察された。図8は、pmIL-12/PPCの腫瘍内注射のGL261脳腫瘍の増殖に対する作用を示す。pIL-12/PPC複合体(N:P比11:1)の局所送達によるマウスGL261グリオーマの頭蓋内移植物の治療は、生存を顕著に亢進した。皮下に移植した頭頸部扁平細胞癌を有するマウスにおいて、1週間に1回、4週間のpmIL-12/PPC複合体の腫瘍内投与により、腫瘍増殖速度の顕著な阻害がもたらされた(図9)。pmIL-12/PPC複合体の抗癌作用は、卵巣腫瘍および乳腺腫瘍でも見いだされた。 These data indicate that a composition comprising an IL-12 expression plasmid and PPC can reveal IL-12 gene transport in different tumor types and by different routes of administration. IL-12 gene transport mediated by pmIL-12 / PPC is therapeutically significant because it causes significant inhibition of tumor growth. In mice with peritoneal disseminated ovarian tumors, intraperitoneal administration of pmIL-12 / PPC complex (N: P ratio 11: 1) at a DNA dose of 10-250 μg significantly reduces tumor burden in a dose-dependent manner (Fig. 5) and improved survival (Fig. 6). The therapeutic effect of pmIL-12 / PPC (N: P ratio 11: 1) was also observed in colorectal cancer. Intraperitoneal administration of 25 μg pmIL-12 / PPC complex in mice with peritoneal diffuse colorectal cancer markedly prolonged their survival compared to untreated animals (FIG. 7). The anticancer effect of IL-12 gene transport by pmIL-12 / PPC was also observed in solid tumors after intratumoral administration. FIG. 8 shows the effect of intratumoral injection of pmIL-12 / PPC on the growth of GL261 brain tumors. Treatment of intracranial implants of mouse GL261 glioma with local delivery of pIL-12 / PPC complex (N: P ratio 11: 1) significantly enhanced survival. In mice with head and neck squamous cell carcinoma implanted subcutaneously, intratumoral administration of the pmIL-12 / PPC complex once a week for 4 weeks resulted in significant inhibition of tumor growth rate (Fig. 9). The anticancer effect of the pmIL-12 / PPC complex was also found in ovarian and breast tumors.
本発明の組成物(核酸および遺伝子送達ポリマー)は、in vivoで投与した場合に、有害な副作用を引き起こさない。たとえば、化合物関連死または毒性の臨床的兆候は何も、腹腔内でまたは皮下での、pmIL-12/PPC投与とは、関係しなかった。pmIL-12/PPCは、オスマウスでもメスマウスでも、動物あたり10、50および250μgに、良好な耐用性であった。IP投与群およびSC投与群の両方における動物の組織病理学的検査から、pmIL-12/PPCによる全身性毒性の証拠は何も示されず、中程度の炎症は、注入部位内にまたは注入部位に隣接して位置する臓器において見られたが、それは1ヶ月の回復期間の間に正常に戻った。これらの結果は、癌の治療のための核酸/ポリマー組成物は、異なる投与様式により投与された場合に幅広い癌に対して有効であり、そして繰り返しin vivo送達により重度の毒性は引き起こされないことが示される。癌に対する単回治療ストラテジーは、この疾患の多因子特性のため、一般的に有効ではないことが広く認識されている。抗癌反応を最大化するための1種以上の薬剤の組み合わせの利点は、徐々に認識されつつある。心強い前臨床データにもかかわらず、これまでに調べられてきた化学物質-化学物質の組み合わせまたは化学物質-サイトカインの組み合わせの臨床的成功は、化学療法薬や組換えサイトカインタンパク質のもともとの毒性のため、満足のいくものではなかった。このことは、タンパク質毒性を縮小し、そして効率を向上させるためのより安全な化学物質-免疫療法のアプローチの必要性を正当化する。本発明において、我々は、化学療法薬を、腫瘍部位に対して局所的に投与され治療の安全性および有効性を向上させる抗癌遺伝子の遺伝子送達と、組み合わせた。抗癌遺伝子の安全で効率的な局所送達を、標準的な化学療法剤と組み合わせることにより、抗癌反応を亢進させ、そして毒性を引き起こすことなく、患者の生存を亢進させる。この組み合わせ治療は、化学療法投与量を減少させ、そして化学療法に対する腫瘍の感受性を上昇させる。本発明において、カチオン性遺伝子送達ポリマーと複合化された抗癌遺伝子、および少なくとも一つの補助的な化学療法薬を含む医薬組成物は、遺伝子治療または化学療法の単独で投与された治療よりも、効果的であることが示される。さらに、組み合わせ治療は、異なる投与経路により投与される場合、幅広い腫瘍に対して有効であり、そして個々の治療に対して毒性を引き起こさない。 The compositions of the invention (nucleic acids and gene delivery polymers) do not cause harmful side effects when administered in vivo. For example, no clinical signs of compound-related death or toxicity were associated with pmIL-12 / PPC administration intraperitoneally or subcutaneously. pmIL-12 / PPC was well tolerated at 10, 50 and 250 μg per animal in both male and female mice. Histopathological examination of animals in both the IP and SC groups showed no evidence of systemic toxicity with pmIL-12 / PPC, and moderate inflammation was in or at the injection site Although seen in adjacent organs, it returned to normal during the 1 month recovery period. These results show that nucleic acid / polymer compositions for the treatment of cancer are effective against a wide range of cancers when administered by different modes of administration, and repeated in vivo delivery does not cause severe toxicity Is shown. It is widely recognized that single treatment strategies for cancer are generally not effective due to the multifactorial nature of the disease. The benefits of the combination of one or more drugs to maximize the anticancer response are gradually being recognized. Despite encouraging preclinical data, the clinical success of chemical-chemical combinations or chemical-cytokine combinations that have been investigated so far is due to the original toxicity of chemotherapeutic drugs and recombinant cytokine proteins. , Was not satisfactory. This justifies the need for a safer chemical-immunotherapy approach to reduce protein toxicity and improve efficiency. In the present invention, we have combined chemotherapeutic drugs with gene delivery of anti-oncogenes that are administered locally to the tumor site to improve the safety and efficacy of the treatment. Combining safe and efficient local delivery of anti-cancer genes with standard chemotherapeutic agents enhances the anti-cancer response and increases patient survival without causing toxicity. This combination therapy reduces chemotherapy dose and increases the tumor's sensitivity to chemotherapy. In the present invention, a pharmaceutical composition comprising an anti-oncogene complexed with a cationic gene delivery polymer and at least one adjuvant chemotherapeutic agent is more effective than gene therapy or chemotherapy administered alone. It is shown to be effective. Furthermore, combination therapy is effective against a wide range of tumors when administered by different routes of administration and does not cause toxicity to individual therapies.
組み合わせ治療に対する抗癌反応は、腹腔内に移植された卵巣腫瘍に対して示される。パクリタキセル(タキソール(登録商標))(8 mg/Kg)の静脈内投与、またはmIL-12プラスミド(25〜100μg)/PPC複合体(N:P比11:1)の腹腔内投与により、腫瘍減少および腫瘍保持マウスにおける生存の改善がもたらされた。pmIL-12/PPC治療は、パクリタキセル治療よりも、効率性が高かった。IL-12遺伝子およびパクリタキセル治療の組み合わせ個々の治療と比較して、より高い治療反応をもたらした(図10)。IL-12遺伝子治療を別の化学療法剤、ゲムシタビン(Gemzar(登録商標))と組み合わせた場合、組み合わせ治療の卵巣癌に対する同様の作用が、観察された(図11)。ゲムシタビンの抗癌活性は、pmIL-12/PPC治療と一緒に使用された場合に、顕著に亢進された。2種の化学療法剤の混合物を用いたIL-12遺伝子治療の組み合わせを調べた。図12に示されるように、IL-12遺伝子治療をカルボプラチン(Paraplatin(登録商標))/パクリタキセルカクテルと組み合わせることにより、結果として、IL-12治療単独または化学療法単独のいずれかと比較して、生存を亢進した。 Anticancer response to combination therapy is demonstrated against ovarian tumors implanted intraperitoneally. Tumor reduction by intravenous administration of paclitaxel (Taxol®) (8 mg / Kg) or intraperitoneal injection of mIL-12 plasmid (25-100 μg) / PPC complex (N: P ratio 11: 1) And improved survival in tumor-bearing mice. The pmIL-12 / PPC treatment was more efficient than the paclitaxel treatment. The combination of IL-12 gene and paclitaxel treatment resulted in a higher therapeutic response compared to the individual treatment (Figure 10). When IL-12 gene therapy was combined with another chemotherapeutic agent, gemcitabine (Gemzar®), a similar effect of combination therapy on ovarian cancer was observed (FIG. 11). The anticancer activity of gemcitabine was significantly enhanced when used with pmIL-12 / PPC treatment. The combination of IL-12 gene therapy with a mixture of two chemotherapeutic agents was investigated. As shown in FIG. 12, combining IL-12 gene therapy with a carboplatin® / paclitaxel cocktail results in survival compared to either IL-12 treatment alone or chemotherapy alone. Was enhanced.
IL-12遺伝子治療の準最適用量のカルボプラチン/パクリタキセルへの添加により、毒性を引き起こすことなく、高化学療法剤用量で達成された治療効果と同様に、治療効果を亢進した(図12)。 Addition of suboptimal doses of IL-12 gene therapy to carboplatin / paclitaxel enhanced the therapeutic effect, similar to that achieved with high chemotherapeutic doses, without causing toxicity (FIG. 12).
組み合わせ治療による抗癌反応における向上もまた、固形腫瘍において観察された。たとえば、頭頸部の皮下扁平上皮癌において、化学療法剤シクロホスファミドの静脈内投与(150 mg/kg)は、腫瘍増殖が顕著に減少したが、しかし完全には阻害しなかった(図13)。pmIL-12/PPC単独の腫瘍内注射により、腫瘍増殖の約30%の阻害が引き起こされた。個々の治療とは対照的に、シクロホスファミド+pmIL-12/PPCの組み合わせ治療により、腫瘍増殖の完全な阻害が引き起こされた。完全な拒絶率は、シクロホスファミドを用いてわずか10%であったのが、シクロホスファミド+pmIL-12/PPC複合体を用いて55%にまで劇的に上昇した。GL261脳腫瘍中への準最適用量(1.5μg)のpmIL-12/PPC複合体の単回腫瘍内注射は、動物の生存率を顕著に亢進しなかった。しかしながら、この準最適用量のpmIL-12/PPCを化学療法剤BCNU(Gliadel(登録商標)wafer)と組み合わせることにより、生存率に顕著な亢進がもたらされた(図14)。 An improvement in anti-cancer response with combination therapy was also observed in solid tumors. For example, in subcutaneous squamous cell carcinoma of the head and neck, intravenous administration of the chemotherapeutic agent cyclophosphamide (150 mg / kg) significantly reduced tumor growth but did not completely inhibit it (Figure 13). ). Intratumoral injection of pmIL-12 / PPC alone caused about 30% inhibition of tumor growth. In contrast to individual treatment, the combined treatment of cyclophosphamide + pmIL-12 / PPC caused complete inhibition of tumor growth. Complete rejection was dramatically increased from only 10% with cyclophosphamide to 55% with cyclophosphamide + pmIL-12 / PPC complex. A single intratumoral injection of a suboptimal dose (1.5 μg) of pmIL-12 / PPC complex into GL261 brain tumors did not significantly enhance animal survival. However, combining this sub-optimal dose of pmIL-12 / PPC with the chemotherapeutic agent BCNU (Gliadel® wafer) resulted in a significant increase in survival (FIG. 14).
高用量の化学療法を用いた癌治療は、重度な毒性と関連している。IL-12/PPCを低用量の化学療法に添加することにより、治療-関連毒性が増大するかどうかを調べるため、腹膜散在性卵巣腫瘍-保持マウスを、IL-12/PPCおよび低用量の化学療法の3回の治療サイクルで治療し(単回治療サイクルと比較して)、そして毒性の兆候をモニタリングした。直接的な比較を、3サイクルの高用量の化学療法治療で治療した動物との間でおこなった。図15に示されるように、50%の高用量の化学療法群は、治療関連毒性のために(すなわち、40グラムに到達する前に)死んだが、IL-12/PPC+低用量の化学療法群は、治療毒性によっては死ななかった。これらの結果から、癌に対する従来からの化学療法(高用量)の毒性は、化学療法用量を低下させることにより、そして安全で効果的なIL-12遺伝子治療を負荷することにより、顕著に減少させることができることが示される。これらのデータは、IL-12プラスミドと新規な遺伝子送達ポリマーを含む前記組成物の抗癌効果を示し、そしてその単一の化学療法剤または化学療法剤混合物によるその増大を示す。組み合わせアプローチは、準最適用量の化学療法処方の効果が、毒性を増加させることなく亢進される方法を提供する。 Cancer treatment with high dose chemotherapy is associated with severe toxicity. To investigate whether the addition of IL-12 / PPC to low-dose chemotherapy increases treatment-related toxicity, peritoneal diffuse ovarian tumor-retaining mice were treated with IL-12 / PPC and low-dose chemistry. Treated with three treatment cycles of therapy (compared to a single treatment cycle) and monitored for signs of toxicity. A direct comparison was made between animals treated with 3 cycles of high dose chemotherapy treatment. As shown in FIG. 15, the 50% high dose chemotherapy group died due to treatment related toxicity (ie, before reaching 40 grams), but the IL-12 / PPC + low dose chemotherapy group Did not die due to therapeutic toxicity. From these results, the toxicity of conventional chemotherapy (high dose) for cancer is significantly reduced by lowering the chemotherapy dose and by loading safe and effective IL-12 gene therapy. It is shown that you can. These data show the anti-cancer effect of the composition comprising IL-12 plasmid and a novel gene delivery polymer and show its increase by its single chemotherapeutic agent or mixture of chemotherapeutic agents. The combined approach provides a way in which the effects of suboptimal dose chemotherapy regimens are enhanced without increasing toxicity.
以下の実施例は、当業者に、本発明をどのようにして実施するかをより明確に理解させるものである。本発明は、その好ましい具体的な態様と組み合わせて記載されたが、それらは本発明を説明することを意図したものであって、本発明の範囲を限定することを意図しないことは、理解されるべきである。本発明のその他の側面が本発明が包含するものであることは、当業者には自明である。 The following examples will enable those skilled in the art to more clearly understand how to practice the present invention. While the invention has been described in combination with preferred specific embodiments thereof, it is understood that they are intended to illustrate the invention and are not intended to limit the scope of the invention. Should be. It will be apparent to those skilled in the art that other aspects of the present invention are encompassed by the present invention.
実施例1 pIL-12/PPC複合体の局所投与による、腹膜散在性腫瘍または皮下腫瘍中へのIL-12遺伝子輸送
pIL-12/PPC複合体の局所的送達が、皮下および腹膜散在性腫瘍保持マウスにおけるIL-12レベルを生成する能力を、調べた。皮下腫瘍研究のためには、メスBALB/cマウス(7週、14-18グラム)マウスに、左側腹部および右側腹部において、それぞれ1×106個の4T1細胞を皮下的に(sc)注射した。腫瘍が60 mm3のおよその腫瘍サイズに到達した後、6μgのDNAを含有するpmIL-12/PPC複合体をマウスに注射した。マウスを、24時間後に犠死させ、そしてそれらの腫瘍を、ELISAによるmIL12解析用に回収した。注射後24時間後の腫瘍中のmIL-12レベルは、図3A中に示される。
Example 1 IL-12 gene transport into peritoneal disseminated or subcutaneous tumors by local administration of pIL-12 / PPC complex
The ability of local delivery of the pIL-12 / PPC complex to generate IL-12 levels in subcutaneous and peritoneal scattered tumor-bearing mice was examined. For subcutaneous tumor studies, female BALB / c mice (7 weeks, 14-18 grams) were injected subcutaneously (sc) with 1 × 10 6 4T1 cells in the left and right flank respectively. . After the tumor reached an approximate tumor size of 60 mm 3 , mice were injected with a pmIL-12 / PPC complex containing 6 μg of DNA. Mice were sacrificed 24 hours later and their tumors were harvested for mIL12 analysis by ELISA. The mIL-12 levels in the
腹膜腫瘍の研究のためには、メスC57/BL6マウスに、500μlの容量中、5×106ID8細胞を、腹腔内(ip)に注射した。腫瘍負荷(マウス重量)が、約20グラムに到達したとき(細胞の注射後約21日後)、治療を開始した。マウスに、500μlの容量中、11:1の窒素(N)対ホスフェート(P)比(N:P比)で、pmIL-12/PPCの単回容量を腹腔内に注射した。マウスをpmIL-12/PPCで処置した後1、2、3および7日後に、腫瘍保持動物から腹水を回収した。mIL-12のレベルおよびIFN-γのレベルは、ELISAにより決定され、そして全腹水に対して正規化された。その結果は、十分なレベルのmIL-12が、腹水中に見られ、ピークレベルが治療後1日後に得られ、そのレベルは治療の7日後までに、ベースライン近くまで落ちてくることを、示す(図3B)。
IFN-γのレベルは、上昇することが同様に見いだされるが、しかしながらピークレベルは、IL-12レベルに対して一時的に遅延し(第3日目のピーク)、そして治療後7日後までに落ち込むが、しかし依然としてベースラインレベルよりも有意に上にあった(図4)。
For the study of peritoneal tumors, female C57 / BL6 mice were injected intraperitoneally (ip) with 5 × 10 6 ID8 cells in a volume of 500 μl. Treatment started when tumor burden (mouse weight) reached approximately 20 grams (approximately 21 days after cell injection). Mice were injected intraperitoneally with a single volume of pmIL-12 / PPC at a 11: 1 nitrogen (N) to phosphate (P) ratio (N: P ratio) in a volume of 500 μl. Ascites fluid was collected from tumor-bearing
The level of IFN-γ is found to rise as well, however, the peak level is temporarily delayed relative to the IL-12 level (
実施例2 pIL-12/PPC複合体の腹腔内投与による、腹膜散在性卵巣腫瘍の治療
マウスに、500μlの容量で、5×106 ID8細胞を腹腔内に注射した。腫瘍負荷(マウス重量)がおよそ20グラムに到達したとき(細胞の注射後約21日後)、治療を開始した。マウスに、500μlの容量中、11:1のN:P比でPPCと複合化された10〜250μgのpIL-12を、1週間に3回、腹腔内に注射した。マウスは、この研究の期間中、定期的に秤量した。体重増加は、主として腹水蓄積により引き起こされ、このことは、疾患の長期化および腫瘍負荷の間接的な評価をもたらす。pmIL-12/PPC治療は、用量依存的な腫瘍負荷の阻害(図5)および動物生存の長期化(図6)をもたらした。
Example 2 Treatment of Peritoneal Scattered Ovarian Tumors by Intraperitoneal Administration of pIL-12 / PPC Complex Mice were injected intraperitoneally with 5 × 10 6 ID8 cells in a volume of 500 μl. Treatment began when tumor burden (mouse weight) reached approximately 20 grams (about 21 days after cell injection). Mice were injected intraperitoneally three times a week with 10-250 μg of pIL-12 complexed with PPC at a 11: 1 N: P ratio in a volume of 500 μl. Mice were weighed regularly throughout the study. Weight gain is mainly caused by ascites accumulation, which leads to prolonged disease and indirect assessment of tumor burden. pmIL-12 / PPC treatment resulted in dose-dependent inhibition of tumor burden (Figure 5) and prolonged animal survival (Figure 6).
実施例3 pIL-12/PPC複合体の腹腔内投与による、腹膜散在性結腸直腸腫瘍の治療
マウスに、500μlの容量中で、0.1×106 CT26細胞を腹腔内に注射した。腫瘍移植後1日後に、治療を開始した。マウスに、500μlの容量中、11:1のN:P比で、PPCと複合化された50μgのpmIL-12、またはLPPC6と複合化された25μgのpIL-12の注射を、1週間に5回、腹腔内に投与した。LPPC6は、15 kDの直鎖ポリエチレンイミンであり、それに対して、1分子のmPEGと6分子のコレステロールが独立して結合している。7に示されるように、pmIL-12/PPCおよびpmIL-12/LPPC6治療により、この非常に転移性の腫瘍モデルにおいて、非処置対照を越える、生存における有意な改善がもたらされた。
Example 3 Treatment of peritoneal disseminated colorectal tumor by intraperitoneal administration of pIL-12 / PPC complex
Mice were injected intraperitoneally with 0.1 × 10 6 CT26 cells in a volume of 500 μl. Treatment started 1 day after tumor implantation. Mice received an injection of 50 μg pmIL-12 complexed with PPC, or 25 μg pIL-12 complexed with LPPC6, in an N: P ratio of 11: 1 in a volume of 500 μl, 5 per week. Administered intraperitoneally. LPPC6 is a 15 kD linear polyethyleneimine to which 1 molecule of mPEG and 6 molecules of cholesterol are independently bound. As shown in 7, pmIL-12 / PPC and pmIL-12 / LPPC6 treatment provided a significant improvement in survival over untreated controls in this highly metastatic tumor model.
実施例4 pIL-12/PPC複合体の腫瘍内投与による、脳の癌の治療
pmIL-12/PPC複合体の局所送達の作用を、マウスグリオーマモデルにおいて調べた。腫瘍を、1×105GL261グリオーマ細胞をpmIL-12/PPC複合体の同時注射と一緒に頭蓋内注射することにより、マウスの大脳皮質内に、移植した。動物を、神経毒性の何らかの徴候をモニタリングし、そして可能であれば剖検して、死が頭蓋内腫瘍によるものであったことを確認した。生存は、Kaplan-Meier生存解析を使用してプロットした。2.5〜30μgのプラスミドの容量範囲で投与したpmIL-12/PPC複合体の単回頭蓋内注射は、顕著な有害作用が何ら見いだされなかったことから、十分に耐用性のものであった。15μgのプラスミドの容量でのpmIL-12/PPC複合体の単回注射により、動物の生存における顕著な亢進がもたらされた(図8)。
Example 4 Treatment of Brain Cancer by Intratumoral Administration of pIL-12 / PPC Complex
The effect of local delivery of pmIL-12 / PPC complex was investigated in a mouse glioma model. Tumors were transplanted into the cerebral cortex of mice by intracranial injection of 1 × 10 5 GL261 glioma cells with simultaneous injection of pmIL-12 / PPC complex. The animals were monitored for any signs of neurotoxicity and necropsied if possible to confirm that the death was due to an intracranial tumor. Survival was plotted using Kaplan-Meier survival analysis. A single intracranial injection of pmIL-12 / PPC complex administered in a volume range of 2.5-30 μg of plasmid was well tolerated as no significant adverse effects were found. A single injection of pmIL-12 / PPC complex at a volume of 15 μg plasmid resulted in a significant increase in animal survival (FIG. 8).
実施例5 pIL-12/PPC複合体の腫瘍内投与による、頭頸部癌の治療
pIL-12/PPC複合体の局所投与の、皮下的に移植した扁平上皮細胞(SCCVII)癌の増殖に対する作用を調べた。100μl中4×105扁平上皮癌細胞を、メスCH3マウス(6〜9週、17〜22グラム)の右側腹部の皮下(sc)に移植した。mIL-12プラスミドを、11:1のN:P比でPPCと複合化させ、そして50μlの注射容量中25μgのDNA投与量で、腫瘍移植後約11日後に開始して、1週間に1回、腫瘍中に局所的に投与した。
Example 5 Treatment of head and neck cancer by intratumoral administration of pIL-12 / PPC complex
The effect of local administration of pIL-12 / PPC complex on the growth of subcutaneously transplanted squamous cell (SCCVII) cancer was examined. 4 × 10 5 squamous cell carcinoma cells in 100 μl were implanted subcutaneously (sc) in the right flank of female CH3 mice (6-9 weeks, 17-22 grams). The mIL-12 plasmid is complexed with PPC at an N: P ratio of 11: 1 and once a week starting approximately 11 days after tumor implantation at a dose of 25 μg of DNA in a 50 μl injection volume. Administered topically in the tumor.
12マウスの治療群を使用して、そして腫瘍増殖をノギス測定を使用して1週間に2回モニタリングした。図9に示されるように、pmIL-12/PPC複合体の腫瘍内投与により、部分的ではあるが顕著な腫瘍増殖の阻害がもたらされた。 A 12-mouse treatment group was used and tumor growth was monitored twice a week using caliper measurements. As shown in FIG. 9, intratumoral administration of the pmIL-12 / PPC complex resulted in partial but significant inhibition of tumor growth.
実施例6 腹膜散在性卵巣腫瘍の治療のための、pIL-12/PPC+パクリタキセルの組み合わせ治療
腹腔内IL-12遺伝子治療を、パクリタキセル化学療法と組み合わせて、マウスにおける散在性卵巣腫瘍に対する治療反応を亢進させた。マウスに、500μlの容量中、5×106ID8細胞を腹腔内に注射した。腫瘍負荷(マウス重量)がおよそ20グラムに到達したとき(細胞の注射後約21日後)、治療を開始した。マウスに、500μlの容量中、11:1のN:P比でPPCと複合化された25μgのpmIL-12を、腹腔内に注射した。1回の研究あたり、全部で2回の注射(Day 1、8)からなる遺伝子治療を、7日後に繰り返した。パクリタキセル(Taxol(登録商標))を、250μLの注入容量中8 mg/kgの容量の投与量で、静脈内注射することにより、1回だけ(Day 0)投与した。組み合わせ治療のため、遺伝子治療と化学療法治療の両方とも、上述したように与えた。動物を定期的に秤量して、腫瘍負荷に対する遺伝子治療の作用を評価した。pmIL-12/PPC複合体単独の腹腔内注射により、腹膜腫瘍負荷の顕著な減少がもたらされた。pmIL-12/PPC複合体による腫瘍負荷の阻害は、パクリタキセルの腫瘍負荷の阻害よりも若干高かった。パクリタキセルに対してIL-12遺伝子治療を追加することにより、腫瘍負荷および生存に対するパクリタキセルの作用において改善が生じた(図10)。
Example 6 pIL-12 / PPC + paclitaxel combination therapy for the treatment of peritoneal disseminated ovarian tumors Intraperitoneal IL-12 gene therapy combined with paclitaxel chemotherapy enhances therapeutic response to disseminated ovarian tumors in mice I let you. Mice were injected intraperitoneally with 5 × 10 6 ID8 cells in a volume of 500 μl. Treatment began when tumor burden (mouse weight) reached approximately 20 grams (about 21 days after cell injection). Mice were injected intraperitoneally with 25 μg pmIL-12 complexed with PPC at a 11: 1 N: P ratio in a volume of 500 μl. Gene therapy consisting of a total of two injections (
実施例7 腹膜散在性卵巣癌の治療のための、pIL-12/PPC+ゲムシタビン組み合わせ治療
IL-12遺伝子治療をゲムシタビン(Gemzar(登録商標))と組み合わせることの効率が、比較された。ゲムシタビンは、代謝拮抗物質として知られる化学療法薬物の一般群に属する。膵臓癌、乳腺癌(パクリタキセルと一緒に)、そして肺癌(シスプラチンによる)、を治療することために使用されるが、卵巣癌に対して使用するために、現在は、臨床的に評価されている。本研究のため、マウス(C57BL/6)に、500μlの容量中、2.5×106ID8細胞で、腹腔内注射して、散在性腫瘍形成を誘導した。腫瘍移植後14日後に、ゲムシタビンを、250μlの容量中、150 mg/kgの用量で、腹腔内に投与した。治療を、全部で4回の治療のために、毎週繰り返した。腫瘍移植後17日後に開始し、マウスの選択された群に、500μlの容量中、11:1のN:P比でPPCと複合化された25μgのIL-12プラスミドを、腹腔内で処置した。プラスミド投与を、全部で4回の治療のために、毎週繰り返した。IL-12遺伝子治療およびゲムシタビン化学療法の組み合わせ治療は、いずれかの単一治療単独での場合と比較して、生存を顕著に改善した(図11)。
Example 7 pIL-12 / PPC + gemcitabine combination treatment for the treatment of peritoneal diffuse ovarian cancer
The efficiency of combining IL-12 gene therapy with gemcitabine (Gemzar®) was compared. Gemcitabine belongs to the general group of chemotherapeutic drugs known as antimetabolites. Used to treat pancreatic cancer, breast cancer (along with paclitaxel), and lung cancer (with cisplatin), but is currently clinically evaluated for use against ovarian cancer . For this study, mice (C57BL / 6) were injected intraperitoneally with 2.5 × 10 6 ID8 cells in a volume of 500 μl to induce disseminated tumor formation. 14 days after tumor implantation, gemcitabine was administered intraperitoneally at a dose of 150 mg / kg in a volume of 250 μl. Treatment was repeated weekly for a total of 4 treatments. Starting 17 days after tumor implantation, selected groups of mice were treated intraperitoneally with 25 μg of IL-12 plasmid complexed with PPC at a 11: 1 N: P ratio in a volume of 500 μl. . Plasmid administration was repeated weekly for a total of 4 treatments. Combined treatment of IL-12 gene therapy and gemcitabine chemotherapy significantly improved survival compared to either single treatment alone (FIG. 11).
実施例8
腹膜散在性卵巣癌の治療のための、pIL-12/PPC+カルボプラチン/パクリタキセルの組み合わせ治療
卵巣癌のための最前線の化学療法は、プラチナ剤(カルボプラチン、シスプラチン)およびパクリタキセルであり続けている。そのため、我々は、IL-12遺伝子治療を、カルボプラチン/パクリタキセル化学療法処方と組み合わせて使用することを評価することに興味を抱いた。マウス(C57BL/6)に、500μlの容量中、2.5×106ID8細胞を腹腔内に注射した。化学療法治療を、腫瘍移植の15日後に開始した。カルボプラチン(Paraplatin(登録商標))投与を、250 ml中40 mg/kgをipで(高用量)または250μl中15 mg/kg(低用量)のいずれかであり、そしてパクリタキセル(Taxol(登録商標))投与を、250μl中8 mg/kgをipで(高用量)または250 ml中3 mg/kgを腹腔内で(低用量)のいずれかで投与した。カルボプラチンは、全部で4回の治療のために1週間に1回投与し、そしてパクリタキセルは、全部で2回の治療のためにq2wで投与した。カルボプラチンおよびパクリタキセルを同日に投与した場合、パクリタキセルを最初に投与し、そして次にカルボプラチンを2時間後に投与した。腫瘍移植後18日後に開始して、選択された群におけるマウスに、500μlの容量中、11:1のN:P比でPPCと複合化された25μgのIL-12プラスミドを、腹腔内に処置した。プラスミド投与を、全部で4回の治療のため、毎週繰り返した。治療処方の終了後、動物を生存についてモニタリングした。この結果から、IL-12遺伝子治療と低用量カルボプラチン/パクリタキセル化学療法の両方により、同様の生存結果がもたらされたことが示される(図12)。低用量化学療法をIL-12遺伝子治療と組み合わせた場合とは対照的に、効率は、高用量化学療法治療処方の効率とほぼ同一のレベルまで改善された。毒性を最小限にするためにより低量の化学療法用量を使用する一方で、治療効率を維持するため、IL-12 遺伝子治療を低用量の化学療法と組み合わせて使用することができることは、好都合である。このことは、非常に高まった治療反応のための機会を提示するため、潜在的に、患者を、長期間のあいだ化学療法治療処方をそのままにしておくことができる。
Example 8
PIL-12 / PPC + carboplatin / paclitaxel combination therapy for the treatment of peritoneal diffuse ovarian cancer The frontline chemotherapy for ovarian cancer continues to be platinum (carboplatin, cisplatin) and paclitaxel. As such, we were interested in evaluating the use of IL-12 gene therapy in combination with carboplatin / paclitaxel chemotherapy regimens. Mice (C57BL / 6) were injected intraperitoneally with 2.5 × 10 6 ID8 cells in a volume of 500 μl. Chemotherapy treatment was started 15 days after tumor transplantation. Carboplatin (Paraplatin®) administration, either 40 mg / kg ip in 250 ml (high dose) or 15 mg / kg in 250 μl (low dose), and paclitaxel (Taxol®) ) Administration was either 8 mg / kg in 250 μl ip (high dose) or 3 mg /
実施例9 頭頸部癌の治療のための、pIL-12/PPC+シクロホスファミドの組み合わせ治療
腫瘍内IL-12遺伝子治療を、シクロホスファミド(Cytoxan(登録商標)化学療法と組み合わせて、頭頸部癌における治療反応を亢進させた。100μl中、4×105扁平上皮癌細胞(SCCVII)を、メスCH3マウス(6〜9週、17〜22グラム)の右側腹部に、皮下に移植した。シクロホスファミド治療の5日前(腫瘍移植のおよそ11日後)、mIL-12プラスミドは、11:1のN:P比でPPCと複合化され、そして50μlの注入容量中25μgのDNA用量で、毎週1回4週間、腫瘍中に局所的に投与した。シクロホスファミド治療を、125μlの注入容量中200 mg/kgの用量を単独で、またはpIL-12遺伝子治療と組み合わせて、静脈内投与した。研究あたり全部で2回の注入からなるシクロホスファミド治療を、14日後に繰り返した。組み合わせ治療のため、遺伝子治療と化学療法治療の両方を、上述したように投与した。12匹のマウスの治療群を使用し、そして腫瘍増殖を、ノギス測定(calliper measurement)を使用して1週間に2回モニタリングした。
Example 9 Combination Treatment of pIL-12 / PPC + Cyclophosphamide for the Treatment of Head and Neck Cancer Intratumoral IL-12 gene therapy in combination with cyclophosphamide (Cytoxan® chemotherapy) In 100 μl, 4 × 10 5 squamous cell carcinoma cells (SCCVII) were implanted subcutaneously into the right flank of female CH3 mice (6-9 weeks, 17-22 grams). Five days before cyclophosphamide treatment (approximately 11 days after tumor implantation), the mIL-12 plasmid was complexed with PPC at an N: P ratio of 11: 1 and at a DNA dose of 25 μg in a 50 μl injection volume, Administered topically once a week for 4 weeks in the tumor: cyclophosphamide treatment intravenously at a dose of 200 mg / kg alone or in combination with pIL-12 gene therapy in a 125 μl infusion volume Cyclophosphamide treatment consisting of a total of 2 injections per study was repeated after 14 days For combination therapy, both gene therapy and chemotherapeutic therapy were administered as described above, using a treatment group of 12 mice and tumor growth using a calliper measurement. Monitored twice a week.
図13に示されるように、pmIL-12/PPC複合体の腫瘍内投与またはシクロホスファミドを単独で静脈内注射により、腫瘍増殖の部分的阻害がもたらされる一方、それらの組み合わせにより、完全な阻害がもたらされた。組み合わせ治療により治療された動物の高い割合が、化学療法単独で治療された動物(10%)とは対照的に、腫瘍を完全に拒絶した(55%)。 As shown in FIG. 13, intratumoral administration of pmIL-12 / PPC complex or intravenous injection of cyclophosphamide alone resulted in partial inhibition of tumor growth, while their combination resulted in complete inhibition. Inhibition was brought about. A high percentage of animals treated with combination therapy completely rejected tumors (55%), in contrast to animals treated with chemotherapy alone (10%).
実施例10 腫瘍内pIL-12/PPCおよびBCNU組み合わせ治療による、脳の癌の治療
pmIL-12/PPC複合体の単独またはBCNU(Gliadel(登録商標))と組み合わせた場合の局所送達の作用を、マウスグリオーマモデルにおいて調べた。Gliadel(登録商標)waferは、カルムスチンまたはBCNU、ニトロソウレアファミリーの化学療法薬のポリマー性製剤である。腫瘍を、1×105GL261グリオーマ細胞を、pmIL-12/PPC複合体の同時注射と一緒に、頭蓋内注射により、マウスの大脳皮質内に移植した。腫瘍移植の5日後、10%BCNUを含有するGliadel(登録商標)を、頭頂骨の内部テーブル下に移植した。動物を、神経毒性の何らかのサインについてモニタリングし、可能であれば剖検し、頭蓋内腫瘍による死を確認した。生存は、Kaplan-Meier生存解析を使用してプロットした。2.5〜30μgのプラスミドの範囲で投与されたpmIL-12/PPC複合体の単回頭蓋内注射は、顕著な有害作用が見いだされなかったため、十分に耐用性であった。1.5μgプラスミド用量で投与されたpmIL-12/PPC複合体の単回注射は、生存率を高めなかった。しかしながら、この準最適な用量でのpmIL-12/PPCとBCNUとの組み合わせにより、顕著に生存が上昇した(図14)。組み合わせ治療からの生存の向上は、このモデルにおいてBCNU単独で歴史的に得られたものよりも高かった(データは示さず)。
Example 10 Treatment of Brain Cancer with Intratumoral pIL-12 / PPC and BCNU Combination Therapy
The effect of local delivery of pmIL-12 / PPC complex alone or in combination with BCNU (Gliadel®) was investigated in a mouse glioma model. Gliadel® wafer is a polymeric formulation of carmustine or BCNU, a nitrosourea family of chemotherapeutic drugs. Tumors were transplanted into the cerebral cortex of mice by intracranial injection of 1 × 10 5 GL261 glioma cells together with co-injection of pmIL-12 / PPC complex. Five days after tumor implantation, Gliadel® containing 10% BCNU was implanted under the internal table of the parietal bone. Animals were monitored for any signs of neurotoxicity and necropsied if possible to confirm death from intracranial tumors. Survival was plotted using Kaplan-Meier survival analysis. A single intracranial injection of pmIL-12 / PPC complex administered in the 2.5-30 μg plasmid range was well tolerated as no significant adverse effects were found. A single injection of pmIL-12 / PPC complex administered at 1.5 μg plasmid dose did not increase survival. However, the combination of pmIL-12 / PPC and BCNU at this suboptimal dose significantly increased survival (FIG. 14). The improvement in survival from combination therapy was higher in this model than that historically obtained with BCNU alone (data not shown).
実施例11 IL-12/PPC+低用量カルボプラチン/パクリタキセル組み合わせ治療の毒性と、高用量カルボプラチン/パクリタキセル組み合わせ治療の毒性の比較
IL-12/PPCを低用量カルボプラチン治療(15 mg/kg)およびパクリタキセル治療(3 mg/kg)と組み合わせることにより、高用量カルボプラチン化学療法(40 mg/kg)およびパクリタキセル化学療法(8 mg/kg)と同様の抗癌効率がもたらされることが、出願人により、以前に示された(実施例8、図12)。この実施例においては、IL-12/PPC+低用量組み合わせ化学療法が、高用量化学療法よりも低毒性であるかどうかを調べる。腹膜散在性卵巣腫瘍を保持するマウスに、以前の例では1回のサイクルのみが使用されたことと比較して、IL-12/PPC+低用量化学療法または高用量化学療法の3回の治療サイクルを投与した。40グラム体重カットオフ(疾患の進行により動物を犠死させるための基準)に到達する前に生じるが、剖検において顕著な腫瘍負荷を示さない動物の死亡率を、治療に関連するものと考えた。マウス(C57BL/6)に、500μlの容量中2.5×106ID8細胞を、腹腔内に注射した。化学療法治療を、腫瘍移植の15日後に開始した。カルボプラチン(Paraplatin(登録商標))の投与を、250 ml中40 mg/kgをipで(高用量)または250μl中15 mg/kgで(低用量)のいずれかで行い、そしてパクリタキセル(Taxol(登録商標))投与を、250μl中8 mg/kgをipで(高用量)または250 ml中3 mg/kgを腹腔内で(低用量)のいずれかで行った。カルボプラチンを全部で4回の治療のため1週間に1回投与し、そしてパクリタキセルを全部で2回の治療のためにq2wで投与した。治療日には、パクリタキセルを最初に投与し、その後2時間後にカルボプラチンを投与した。腫瘍移植後18日後に開始して、選択された群におけるマウスに、500μlの容量中、11:1のN:P比でPPCと複合化された100μgのIL-12プラスミドを、腹腔内に処置した。プラスミド投与を、全部で4回の治療のため、毎週繰り返した。完全な治療サイクルを3回繰り返し(全部で12週間)、そして動物を生存についてモニタリングした。IL-12/PPC+低用量化学療法群、低用量化学療法群、またはIL-12/PPCのみの治療群においては治療に関連する死が0%であったのに対して、図15において示されるように、30%の高用量化学療法群は、治療に関連する毒性により(すなわち、40グラムに到達する前に)死んだ。これらの結果から、高用量化学療法処方と比較して、IL-12/PPCを低用量化学療法と組み合わせることにより、治療に関連する死が相対的に少なくなり、しかし同様の抗癌効果をもたらすことが示される(図12)。
Example 11 Comparison of Toxicity of IL-12 / PPC + Low Dose Carboplatin / Paclitaxel Combination Treatment with Toxicity of High Dose Carboplatin / Paclitaxel Combination Treatment
High dose carboplatin chemotherapy (40 mg / kg) and paclitaxel chemotherapy (8 mg / kg) by combining IL-12 / PPC with low dose carboplatin treatment (15 mg / kg) and paclitaxel treatment (3 mg / kg) The applicant has previously shown that anti-cancer efficiency is similar to (Example 8, FIG. 12). In this example, it is examined whether IL-12 / PPC + low dose combination chemotherapy is less toxic than high dose chemotherapy. Three treatment cycles of IL-12 / PPC plus low-dose or high-dose chemotherapy compared to the previous example where only one cycle was used for mice with peritoneal diffuse ovarian tumors Was administered. We considered treatment-related mortality in animals that occurred before reaching the 40-gram body weight cut-off (criteria for sacrificing animals due to disease progression) but did not show significant tumor burden at necropsy . Mice (C57BL / 6) were injected intraperitoneally with 2.5 × 10 6 ID8 cells in a volume of 500 μl. Chemotherapy treatment was started 15 days after tumor transplantation. Carboplatin (Paraplatin®) is administered at either 40 mg / kg in 250 ml ip (high dose) or 15 mg / kg in 250 μl (low dose) and paclitaxel (Taxol® The administration was either 8 mg / kg ip in 250 μl (high dose) or 3 mg /
上述した態様は、単に本発明の原理の応用の説明であると理解されるべきである。多数の修飾および代替的態様を、本発明の概念および範囲から離れることなく導き出すことができ、そして添付する請求の範囲は、その様な修飾および配置をカバーすることを意図する。このように、本発明は、現在のところ本発明の最も現実的なそして(1または複数の)好ましい態様とみなされるものと関連して、図面中に示され、そして具体的かつ詳細に完全に上述されているが、一方、本発明の原理および概念から離れることなく多数の修飾を行うことができることは、当業者にとっては自明である。 It should be understood that the above-described aspects are merely illustrative of the application of the principles of the present invention. Numerous modifications and alternative embodiments can be derived without departing from the concept and scope of the present invention, and the appended claims are intended to cover such modifications and arrangements. Thus, the present invention is shown in the drawings and is fully and concretely detailed in connection with what is presently considered to be the most realistic and preferred embodiment (s) of the present invention. While described above, it will be apparent to those skilled in the art that numerous modifications can be made without departing from the principles and concepts of the invention.
Claims (13)
を有する、請求項1または2に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2 , wherein the polyethyleneimine has a linear or branched structure having a molecular weight of 100-500,000 daltons.
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AU2005314468B2 (en) | 2011-03-17 |
ES2380107T3 (en) | 2012-05-08 |
CA2590160A1 (en) | 2006-06-15 |
HK1117345A1 (en) | 2009-01-16 |
US9468687B2 (en) | 2016-10-18 |
AU2005314468A1 (en) | 2006-06-15 |
WO2006062723A3 (en) | 2006-08-17 |
CN101111154B (en) | 2013-03-27 |
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